Статті в журналах: "Genome caretakers"

1

Curcio, M. Joan, Alison E. Kenny, Sharon Moore, David J. Garfinkel, Matthew Weintraub, Eric R. Gamache, and Derek T. Scholes. "S-Phase Checkpoint Pathways Stimulate the Mobility of the Retrovirus-Like Transposon Ty1." Molecular and Cellular Biology 27, no. 24 (October 8, 2007): 8874–85. http://dx.doi.org/10.1128/mcb.01095-07.

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ABSTRACT The mobility of the Ty1 retrotransposon in the yeast Saccharomyces cerevisiae is restricted by a large collection of proteins that preserve the integrity of the genome during replication. Several of these repressors of Ty1 transposition (Rtt)/genome caretakers are orthologs of mammalian retroviral restriction factors. In rtt/genome caretaker mutants, levels of Ty1 cDNA and mobility are increased; however, the mechanisms underlying Ty1 hypermobility in most rtt mutants are poorly characterized. Here, we show that either or both of two S-phase checkpoint pathways, the replication stress pathway and the DNA damage pathway, partially or strongly stimulate Ty1 mobility in 19 rtt/genome caretaker mutants. In contrast, neither checkpoint pathway is required for Ty1 hypermobility in two rtt mutants that are competent for genome maintenance. In rtt101Δ mutants, hypermobility is stimulated through the DNA damage pathway components Rad9, Rad24, Mec1, Rad53, and Dun1 but not Chk1. We provide evidence that Ty1 cDNA is not the direct target of the DNA damage pathway in rtt101Δ mutants; instead, levels of Ty1 integrase and reverse transcriptase proteins, as well as reverse transcriptase activity, are significantly elevated. We propose that DNA lesions created in the absence of Rtt/genome caretakers trigger S-phase checkpoint pathways to stimulate Ty1 reverse transcriptase activity.

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2

Chu, Wai Kit, and Ian D. Hickson. "RecQ helicases: multifunctional genome caretakers." Nature Reviews Cancer 9, no. 9 (August 6, 2009): 644–54. http://dx.doi.org/10.1038/nrc2682.

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3

Hickson, Ian D. "RecQ helicases: caretakers of the genome." Nature Reviews Cancer 3, no. 3 (March 2003): 169–78. http://dx.doi.org/10.1038/nrc1012.

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4

Cunningham, Richard P. "DNA repair: Caretakers of the genome?" Current Biology 7, no. 9 (September 1997): R576—R579. http://dx.doi.org/10.1016/s0960-9822(06)00286-7.

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5

Lahue, Robert S., and Aisling Frizzell. "Histone deacetylase complexes as caretakers of genome stability." Epigenetics 7, no. 8 (August 18, 2012): 806–10. http://dx.doi.org/10.4161/epi.20922.

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6

Gening, L. V., A. V. Makarova, A. M. Malashenko, and V. Z. Tarantul. "A false note of DNA polymerase iota in the choir of genome caretakers in mammals." Biochemistry (Moscow) 71, no. 2 (February 2006): 155–59. http://dx.doi.org/10.1134/s0006297906020064.

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7

Fernández-Bellon, Hugo, Jordi Rodon, Leira Fernández-Bastit, Vanessa Almagro, Pilar Padilla-Solé, Cristina Lorca-Oró, Rosa Valle, et al. "Monitoring Natural SARS-CoV-2 Infection in Lions (Panthera leo) at the Barcelona Zoo: Viral Dynamics and Host Responses." Viruses 13, no. 9 (August 25, 2021): 1683. http://dx.doi.org/10.3390/v13091683.

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To date, no evidence supports the fact that animals play a role in the epidemiology of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the coronavirus infectious disease 2019 (COVID-19). However, several animal species are naturally susceptible to SARS-CoV-2 infection. Besides pets (cats, dogs, Syrian hamsters, and ferrets) and farm animals (minks), different zoo animal species have tested positive for SARS-CoV-2 (large felids and non-human primates). After the summer of 2020, a second wave of SARS-CoV-2 infection occurred in Barcelona (Spain), reaching a peak of positive cases in November. During that period, four lions (Panthera leo) at the Barcelona Zoo and three caretakers developed respiratory signs and tested positive for the SARS-CoV-2 antigen. Lion infection was monitored for several weeks and nasal, fecal, saliva, and blood samples were taken at different time-points. SARS-CoV-2 RNA was detected in nasal samples from all studied lions and the viral RNA was detected up to two weeks after the initial viral positive test in three out of four animals. The SARS-CoV-2 genome was also detected in the feces of animals at different times. Virus isolation was successful only from respiratory samples of two lions at an early time-point. The four animals developed neutralizing antibodies after the infection that were detectable four months after the initial diagnosis. The partial SARS-CoV-2 genome sequence from one animal caretaker was identical to the sequences obtained from lions. Chronology of the events, the viral dynamics, and the genomic data support human-to-lion transmission as the origin of infection.

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8

Gening, L. V., A. V. Makarova, A. M. Malashenko, and V. Z. Tarantul. "Erratum to: A false note of DNA polymerase iota in the choir of genome caretakers in mammals." Biochemistry (Moscow) 74, no. 1 (January 2009): 115. http://dx.doi.org/10.1134/s0006297909010209.

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9

Sangkachai, Nareerat, Somjit Chaiwattanarungruengpaisan, Metawee Thongdee, Parut Suksai, Siriporn Tangsudjai, Peerawat Wongluechai, Sarin Suwanpakdee, et al. "Serological and Molecular Surveillance for SARS-CoV-2 Infection in Captive Tigers (Panthera tigris), Thailand." Animals 12, no. 23 (November 29, 2022): 3350. http://dx.doi.org/10.3390/ani12233350.

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Coronavirus disease (COVID-19) is an emerging infectious disease caused by SARS-CoV-2. Given the emergence of SARS-CoV-2 variants, continuous surveillance of SARS-CoV-2 in animals is important. To monitor SARS-CoV-2 infection in wildlife in Thailand, we collected 62 blood samples and nine nasal- and rectal-swab samples from captive tigers (Panthera tigris) in Ratchaburi province in Thailand during 2020–2021. A plaque reduction neutralization test (PRNT) was employed to detect SARS-CoV-2 neutralizing antibodies. A real-time RT-PCR assay was performed to detect SARS-CoV-2 RNA. Our findings demonstrated that four captive tigers (6.5%, 4/62) had SARS-CoV-2 neutralizing antibodies against Wuhan Hu-1 and the Delta variant, while no SARS-CoV-2 RNA genome could be detected in all swab samples. Moreover, a low-level titer of neutralizing antibodies against the Omicron BA.2 subvariant could be found in only one seropositive tiger. The source of SARS-CoV-2 infection in these tigers most likely came from close contact with the infected animals’ caretakers who engaged in activities such as tiger petting and feeding. In summary, we described the first case of natural SARS-CoV-2 infection in captive tigers during the COVID-19 outbreak in Thailand and provided seroepidemiological-based evidence of human-to-animal transmission. Our findings highlight the need for continuous surveillance of COVID-19 among the captive tiger population and emphasize the need to adopt a One Health approach for preventing and controlling outbreaks of COVID-19 zoonotic disease.

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10

Leon, I. M., S. D. Lawhon, K. N. Norman, D. S. Threadgill, N. Ohta, J. Vinasco, and H. M. Scott. "Serotype Diversity and Antimicrobial Resistance amongSalmonella entericaIsolates from Patients at an Equine Referral Hospital." Applied and Environmental Microbiology 84, no. 13 (April 20, 2018): e02829-17. http://dx.doi.org/10.1128/aem.02829-17.

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ABSTRACTAlthoughSalmonella entericacan produce life-threatening colitis in horses, certain serotypes are more commonly associated with clinical disease. Our aim was to evaluate the proportional morbidity attributed to different serotypes, as well as the phenotypic and genotypic antimicrobial resistance (AMR) ofSalmonellaisolates from patients at an equine referral hospital in the southern United States. A total of 255Salmonellaisolates was obtained from clinical samples of patients admitted to the hospital between 2007 and 2015. Phenotypic resistance to 14 antibiotics surveilled by the U.S. National Antimicrobial Resistance Monitoring System was determined using a commercially available panel. Whole-genome sequencing was used to identify serotypes and genotypic AMR. The most common serotypes wereSalmonella entericaserotype Newport (18%),Salmonella entericaserotype Anatum (15.2%), andSalmonella entericaserotype Braenderup (11.8%). Most (n= 219) of the isolates were pansusceptible, while 25 were multidrug resistant (≥3 antimicrobial classes). Genes encoding beta-lactam resistance, such asblaCMY-2,blaSHV-12,blaCTX-M-27, andblaTEM-1B, were detected. TheqnrB2 andaac(6′)-Ib-crgenes were present in isolates with reduced susceptibility to ciprofloxacin. Genes encoding resistance to gentamicin (aph(3′)-Ia,aac(6′)-IIc), streptomycin (strA andstrB), sulfonamides (sul1), trimethoprim (dfrA), phenicols (catA), tetracyclines [tet(A) andtet(E)], and macrolides [ere(A)] were also identified. The main predicted incompatibility plasmid type was I1 (10%). Core genome-based analyses revealed phylogenetic associations between isolates of common serotypes. The presence of AMRSalmonellain equine patients increases the risk of unsuccessful treatment and causes concern for potential zoonotic transmission to attending veterinary personnel, animal caretakers, and horse owners. Understanding the epidemiology ofSalmonellain horses admitted to referral hospitals is important for the prevention, control, and treatment of salmonellosis.IMPORTANCEIn horses, salmonellosis is a leading cause of life-threatening colitis. At veterinary teaching hospitals, nosocomial outbreaks can increase the risk of zoonotic transmission, lead to restrictions on admissions, impact hospital reputation, and interrupt educational activities. The antimicrobials most often used in horses are included in the 5th revision of the World Health Organization's list of critically important antimicrobials for human medicine. Recent studies have demonstrated a trend of increasing bacterial resistance to drugs commonly used to treatSalmonellainfections. In this study, we identify temporal trends in the distribution ofSalmonellaserotypes and their mechanisms of antimicrobial resistance; furthermore, we are able to determine the likely origin of several temporal clusters of infection by using whole-genome sequencing. These data can be used to focus strategies to better contain the dissemination and enhance the mitigation ofSalmonellainfections and to provide evidence-based policies and guidelines to steward antimicrobial use in veterinary medicine.

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11

Levitt, Nicola C., and Ian D. Hickson. "Caretaker tumour suppressor genes that defend genome integrity." Trends in Molecular Medicine 8, no. 4 (April 2002): 179–86. http://dx.doi.org/10.1016/s1471-4914(02)02298-0.

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12

Waters, Catherine E., Joshua C. Saldivar, Seyed Ali Hosseini, and Kay Huebner. "The FHIT gene product: tumor suppressor and genome “caretaker”." Cellular and Molecular Life Sciences 71, no. 23 (October 5, 2014): 4577–87. http://dx.doi.org/10.1007/s00018-014-1722-0.

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13

Schrock, Morgan S., Jenna R. Karras, Matthew J. Guggenbiller, Teresa Druck, Bahadir Batar, and Kay Huebner. "Fhit and Wwox loss-associated genome instability: A genome caretaker one-two punch." Advances in Biological Regulation 63 (January 2017): 167–76. http://dx.doi.org/10.1016/j.jbior.2016.09.008.

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14

Valenzuela, Martina, Roberta Amato, Antonella Sgura, Antonio Antoccia, and Francesco Berardinelli. "The Multiple Facets of ATRX Protein." Cancers 13, no. 9 (May 5, 2021): 2211. http://dx.doi.org/10.3390/cancers13092211.

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ATRX gene codifies for a protein member of the SWI-SNF family and was cloned for the first time over 25 years ago as the gene responsible for a rare developmental disorder characterized by α-thalassemia and intellectual disability called Alpha Thalassemia/mental Retardation syndrome X-linked (ATRX) syndrome. Since its discovery as a helicase involved in alpha-globin gene transcriptional regulation, our understanding of the multiple roles played by the ATRX protein increased continuously, leading to the recognition of this multifaceted protein as a central “caretaker” of the human genome involved in cancer suppression. In this review, we report recent advances in the comprehension of the ATRX manifold functions that encompass heterochromatin epigenetic regulation and maintenance, telomere function, replicative stress response, genome stability, and the suppression of endogenous transposable elements and exogenous viral genomes.

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15

Karras, Jenna R., Morgan S. Schrock, Bahadir Batar, and Kay Huebner. "Fragile Genes That Are Frequently Altered in Cancer: Players Not Passengers." Cytogenetic and Genome Research 150, no. 3-4 (2016): 208–16. http://dx.doi.org/10.1159/000455753.

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FHIT, located at FRA3B, is one of the most commonly deleted genes in human cancers, and loss of FHIT protein is one of the earliest events in cancer initiation. However, location of FHIT at a chromosomal fragile site, a locus prone to breakage and gap formation under even mild replication stress, has encouraged claims that FHIT loss is a passenger event in cancers. We summarize accumulated evidence that FHIT protein functions as a genome “caretaker” required to protect the stability of genomes of normal cells of most tissues from agents causing intrinsic and extrinsic DNA damage. FHIT loss leads to intracellular replication stress and subsequent genome instability, which provides an opportunistic mutational landscape in preneoplasias for selection of a variety of other cancer-driving mutations. We also review evidence showing that FHIT loss leads to enhanced activation of other common fragile sites, including the FRA16D/WWOX locus, and creates optimal single-stranded DNA substrates for the hypermutator enzyme, APOBEC3B.

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16

Kondo, Yutaka. "Genome–Epigenome–Senescence: Is TET1 a Caretaker of p53-Injured Lung Cancer Cells?" Cancer Research 79, no. 8 (April 15, 2019): 1751–52. http://dx.doi.org/10.1158/0008-5472.can-19-0645.

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17

Tollis, Marc, Aika K. Schneider-Utaka, and Carlo C. Maley. "The Evolution of Human Cancer Gene Duplications across Mammals." Molecular Biology and Evolution 37, no. 10 (May 18, 2020): 2875–86. http://dx.doi.org/10.1093/molbev/msaa125.

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Abstract Cancer is caused by genetic alterations that affect cellular fitness, and multicellular organisms have evolved mechanisms to suppress cancer such as cell cycle checkpoints and apoptosis. These pathways may be enhanced by the addition of tumor suppressor gene paralogs or deletion of oncogenes. To provide insights to the evolution of cancer suppression across the mammalian radiation, we estimated copy numbers for 548 human tumor suppressor gene and oncogene homologs in 63 mammalian genome assemblies. The naked mole rat contained the most cancer gene copies, consistent with the extremely low rates of cancer found in this species. We found a positive correlation between a species’ cancer gene copy number and its longevity, but not body size, contrary to predictions from Peto’s Paradox. Extremely long-lived mammals also contained more copies of caretaker genes in their genomes, suggesting that the maintenance of genome integrity is an essential form of cancer prevention in long-lived species. We found the strongest association between longevity and copy numbers of genes that are both germline and somatic tumor suppressor genes, suggesting that selection has acted to suppress both hereditary and sporadic cancers. We also found a strong relationship between the number of tumor suppressor genes and the number of oncogenes in mammalian genomes, suggesting that complex regulatory networks mediate the balance between cell proliferation and checks on tumor progression. This study is the first to investigate cancer gene expansions across the mammalian radiation and provides a springboard for potential human therapies based on evolutionary medicine.

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18

Mazian, Muadz Ahmad, Kumpei Yamanishi, Mohd Zulhilmi Abdul Rahman, Menega Ganasen, and Hideo Nishitani. "CRL4Cdt2 Ubiquitin Ligase, A Genome Caretaker Controlled by Cdt2 Binding to PCNA and DNA." Genes 13, no. 2 (January 29, 2022): 266. http://dx.doi.org/10.3390/genes13020266.

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The ubiquitin ligase CRL4Cdt2 plays a vital role in preserving genomic integrity by regulating essential proteins during S phase and after DNA damage. Deregulation of CRL4Cdt2 during the cell cycle can cause DNA re-replication, which correlates with malignant transformation and tumor growth. CRL4Cdt2 regulates a broad spectrum of cell cycle substrates for ubiquitination and proteolysis, including Cdc10-dependent transcript 1 or Chromatin licensing and DNA replication factor 1 (Cdt1), histone H4K20 mono-methyltransferase (Set8) and cyclin-dependent kinase inhibitor 1 (p21), which regulate DNA replication. However, the mechanism it operates via its substrate receptor, Cdc10-dependent transcript 2 (Cdt2), is not fully understood. This review describes the essential features of the N-terminal and C-terminal parts of Cdt2 that regulate CRL4 ubiquitination activity, including the substrate recognition domain, intrinsically disordered region (IDR), phosphorylation sites, the PCNA-interacting protein-box (PIP) box motif and the DNA binding domain. Drugs targeting these specific domains of Cdt2 could have potential for the treatment of cancer.

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19

Mistry, Helena, Laura Tamblyn, Hussein Butt, Daniel Sisgoreo, Aileen Gracias, Meghan Larin, Kalpana Gopalakrishnan, Manoor Hande та John McPherson. "UHRF1 is a genome caretaker that facilitates the DNA damage response to γ-irradiation". Genome Integrity 1, № 1 (2010): 7. http://dx.doi.org/10.1186/2041-9414-1-7.

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20

Le, Hang Phuong, Wolf-Dietrich Heyer, and Jie Liu. "Guardians of the Genome: BRCA2 and Its Partners." Genes 12, no. 8 (August 10, 2021): 1229. http://dx.doi.org/10.3390/genes12081229.

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The tumor suppressor BRCA2 functions as a central caretaker of genome stability, and individuals who carry BRCA2 mutations are predisposed to breast, ovarian, and other cancers. Recent research advanced our mechanistic understanding of BRCA2 and its various interaction partners in DNA repair, DNA replication support, and DNA double-strand break repair pathway choice. In this review, we discuss the biochemical and structural properties of BRCA2 and examine how these fundamental properties contribute to DNA repair and replication fork stabilization in living cells. We highlight selected BRCA2 binding partners and discuss their role in BRCA2-mediated homologous recombination and fork protection. Improved mechanistic understanding of how BRCA2 functions in genome stability maintenance can enable experimental evidence-based evaluation of pathogenic BRCA2 mutations and BRCA2 pseudo-revertants to support targeted therapy.

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21

Kim, Jeongkyu, Philipp Oberdoerffer, and Simran Khurana. "The histone variant macroH2A1 is a splicing-modulated caretaker of genome integrity and tumor growth." Molecular & Cellular Oncology 5, no. 3 (April 4, 2018): e1441629. http://dx.doi.org/10.1080/23723556.2018.1441629.

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22

Spicer, James, Åslaug Helland, Enric Carcereny, Edurne Arriola, Manuel Dómine Gomez, Jose Manuel Trigo Perez, Jonathan Thompson, et al. "362 A PhII study of bemcentinib, a first-in-class selective AXL kinase inhibitor, in combination with pembrolizumab in pts with previously-treated advanced NSCLC: Updated clinical & translational analysis." Journal for ImmunoTherapy of Cancer 8, Suppl 3 (November 2020): A387. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0362.

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BackgroundAXL is implicated in resistance to immunotherapy. Bemcentinib (BGB324), a first-in-class, oral, selective and potent AXL kinase inhibitor, enhances checkpoint inhibitor (CPI) efficacy in pre-clinical models through tumor-immune mechanisms.MethodsBGBC008 is a PhII single-arm, 2-stage study with bemcentinib (200 mg/d) and pembrolizumab (200 mg/q3wk) for previously-treated stage IV lung adenocarcinoma comprising 3 cohorts: chemotherapy-pretreated IO-naïve patients (Cohort-A), patients progressing on prior IO therapy (Cohort-B) or chemotherapy/pembrolizumab combination (Cohort-C). Primary endpoint was ORR according to RECIST1.1 with pre-defined criteria to proceed from the first to second stage in each cohort. Secondary endpoints included DCR, PFS, OS and safety. Exploratory endpoints include biomarker analysis and correlation with clinical endpoints, including composite (tumor and immune cell) cAXL score, PD-L1 TPS, and genome-wide mutational and transcriptome analyses.ResultsAs of July 2020, enrollment in Cohort-A and-B (stage 1) is completed; a total of 66 NSCLC patients were dosed. Cohort-A (n=50) results were previously presented. All Cohort-B1 (n=16) patients received at least one prior line of therapy, the most recent including CPI; 4 patients had 1 and 12 had 2+ prior treatments. Of the Cohort-B1 patients, cAXL status was available for 13 patients: 8 cAXL-positive, 5 cAXL-negative. PD-L1 TPS was available for 13 patients: 5 TPS >50%, 5 TPS 1–49%, and 3 TPS <1%. Of patients who had previously undergone 1 line of CPI therapy (n=4), 75% were cAXL-positive and 25% were not evaluable for cAXL (median TPS of 20%). Patients who had previously undergone 2+ lines of therapy (n=12), 33% were cAXL-positive, 50% cAXL-negative, and 17% not evaluable for cAXL(median TPS of 50%). Of the treated pts, most common TEAEs (>25% of patients) were increased ALT (29%; 10% G3+), AST (29%; 5% G3+), and diarrhoea (29%; 1% G3+). All cases of treatment-related transaminase increase were reversible and managed with concomitant administration of steroids and treatment interruption. Of the 15 radiologically-evaluable patients in Cohort-B1, 1 PR was observed; 6/7 (86%) cAXL-positive patients (1 PR, 5 SD) achieved clinical benefit while none was observed in cAXL negative patients. mPFS was 4.7mo in cAXL-positive and 1.9mo in cAXL-negative patients. Ongoing transcriptional analysis of pre-treatment biopsies revealed a distinct gene profile correlating with clinical benefit from bemcentinib + pembrolizumab combination treatment.ConclusionsOverall, bemcentinib in combination with pembrolizumab was well-tolerated and shows promising clinical activity in AXL-positive immunotherapy refractory disease. Updated survival and translation/biomarker data will be presented.AcknowledgementsThe authors would like to thank all patients and their caretakers for participating in this trial.Trial RegistrationNCT03184571Ethics ApprovalThis study was approved by all relevant institutions, including London Bridge Research Ethics Committee (UK), REC-South East (Norway), Drug Research Ethics Committee of the University Hospital Clinic of Barcelona (Spain), MCW/FH Institutional Review Board #4, Medical College of Wisconsin (USA).

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23

Mannini, Linda, Stefania Menga, and Antonio Musio. "The expanding universe of cohesin functions: a new genome stability caretaker involved in human disease and cancer." Human Mutation 31, no. 6 (April 6, 2010): 623–30. http://dx.doi.org/10.1002/humu.21252.

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24

Larsen, Dorthe Helena, Catherine Poinsignon, Thorkell Gudjonsson, Christoffel Dinant, Mark R. Payne, Flurina J. Hari, Jannie M. Rendtlew Danielsen, et al. "The chromatin-remodeling factor CHD4 coordinates signaling and repair after DNA damage." Journal of Cell Biology 190, no. 5 (August 30, 2010): 731–40. http://dx.doi.org/10.1083/jcb.200912135.

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In response to ionizing radiation (IR), cells delay cell cycle progression and activate DNA repair. Both processes are vital for genome integrity, but the mechanisms involved in their coordination are not fully understood. In a mass spectrometry screen, we identified the adenosine triphosphate–dependent chromatin-remodeling protein CHD4 (chromodomain helicase DNA-binding protein 4) as a factor that becomes transiently immobilized on chromatin after IR. Knockdown of CHD4 triggers enhanced Cdc25A degradation and p21Cip1 accumulation, which lead to more pronounced cyclin-dependent kinase inhibition and extended cell cycle delay. At DNA double-strand breaks, depletion of CHD4 disrupts the chromatin response at the level of the RNF168 ubiquitin ligase, which in turn impairs local ubiquitylation and BRCA1 assembly. These cell cycle and chromatin defects are accompanied by elevated spontaneous and IR-induced DNA breakage, reduced efficiency of DNA repair, and decreased clonogenic survival. Thus, CHD4 emerges as a novel genome caretaker and a factor that facilitates both checkpoint signaling and repair events after DNA damage.

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Mangerich, Aswin, and Alexander Bürkle. "Pleiotropic Cellular Functions of PARP1 in Longevity and Aging: Genome Maintenance Meets Inflammation." Oxidative Medicine and Cellular Longevity 2012 (2012): 1–19. http://dx.doi.org/10.1155/2012/321653.

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Aging is a multifactorial process that depends on diverse molecular and cellular mechanisms, such as genome maintenance and inflammation. The nuclear enzyme poly(ADP-ribose) polymerase 1 (PARP1), which catalyzes the synthesis of the biopolymer poly(ADP-ribose), exhibits an essential role in both processes. On the one hand, PARP1 serves as a genomic caretaker as it participates in chromatin remodelling, DNA repair, telomere maintenance, resolution of replicative stress, and cell cycle control. On the other hand, PARP1 acts as a mediator of inflammation due to its function as a regulator of NF-κB and other transcription factors and its potential to induce cell death. Consequently, PARP1 represents an interesting player in several aging mechanisms and is discussed as a longevity assurance factor on the one hand and an aging-promoting factor on the other hand. Here, we review the molecular mechanisms underlying the various roles of PARP1 in longevity and aging with special emphasis on cellular studies and we briefly discuss the results in the context ofin vivostudies in mice and humans.

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26

Utsumi, Takako, Rury Mega Wahyuni, Maria Inge Lusida, Yoshihiko Yano, Nur Purba Priambada, Mochamad Amin, Priyo Budi Purwono, et al. "Full genome characterization and phylogenetic analysis of hepatitis B virus in gibbons and a caretaker in Central Kalimantan, Indonesia." Archives of Virology 160, no. 3 (January 7, 2015): 685–92. http://dx.doi.org/10.1007/s00705-014-2323-9.

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27

Danielsen, Jannie Rendtlew, Lou Klitgaard Povlsen, Bine Hare Villumsen, Werner Streicher, Jakob Nilsson, Mats Wikström, Simon Bekker-Jensen, and Niels Mailand. "DNA damage–inducible SUMOylation of HERC2 promotes RNF8 binding via a novel SUMO-binding Zinc finger." Journal of Cell Biology 197, no. 2 (April 16, 2012): 179–87. http://dx.doi.org/10.1083/jcb.201106152.

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Nonproteolytic ubiquitylation of chromatin surrounding deoxyribonucleic acid (DNA) double-strand breaks (DSBs) by the RNF8/RNF168/HERC2 ubiquitin ligases facilitates restoration of genome integrity by licensing chromatin to concentrate genome caretaker proteins near the lesions. In parallel, SUMOylation of so-far elusive upstream DSB regulators is also required for execution of this ubiquitin-dependent chromatin response. We show that HERC2 and RNF168 are novel DNA damage–dependent SUMOylation targets in human cells. In response to DSBs, both HERC2 and RNF168 were specifically modified with SUMO1 at DSB sites in a manner dependent on the SUMO E3 ligase PIAS4. SUMOylation of HERC2 was required for its DSB-induced association with RNF8 and for stabilizing the RNF8–Ubc13 complex. We also demonstrate that the ZZ Zinc finger in HERC2 defined a novel SUMO-specific binding module, which together with its concomitant SUMOylation and T4827 phosphorylation promoted binding to RNF8. Our findings provide novel insight into the regulatory complexity of how ubiquitylation and SUMOylation cooperate to orchestrate protein interactions with DSB repair foci.

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Kato, Shunsuke. "Tumour-Agnostic Therapy for Pancreatic Cancer and Biliary Tract Cancer." Diagnostics 11, no. 2 (February 6, 2021): 252. http://dx.doi.org/10.3390/diagnostics11020252.

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The prognosis of patients with solid tumours has remarkably improved with the development of molecular-targeted drugs and immune checkpoint inhibitors. However, the improvements in the prognosis of pancreatic cancer and biliary tract cancer is delayed compared to other carcinomas, and the 5-year survival rates of distal-stage disease are approximately 10 and 20%, respectively. However, a comprehensive analysis of tumour cells using The Cancer Genome Atlas (TCGA) project has led to the identification of various driver mutations. Evidently, few mutations exist across organs, and basket trials targeting driver mutations regardless of the primary organ are being actively conducted. Such basket trials not only focus on the gate keeper-type oncogene mutations, such as HER2 and BRAF, but also focus on the caretaker-type tumour suppressor genes, such as BRCA1/2, mismatch repair-related genes, which cause hereditary cancer syndrome. As oncogene panel testing is a vital approach in routine practice, clinicians should devise a strategy for improved understanding of the cancer genome. Here, the gene mutation profiles of pancreatic cancer and biliary tract cancer have been outlined and the current status of tumour-agnostic therapy in these cancers has been reported.

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Douglas, Suvi, Atte Lahtinen, Jessica Koski, Lilli Leimi, Mikko A. Keränen, Kimmo Porkka, Caroline A. Heckman, Kirsi Jahnukainen, Outi Kilpivaara, and Ulla Wartiovaara-Kautto. "Germline Gene Aberrations Are Common in High-Risk Adult and Pediatric Acute Lymphoblastic Leukemia Patients." Blood 134, Supplement_1 (November 13, 2019): 1472. http://dx.doi.org/10.1182/blood-2019-126657.

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Personalized medicine involves a comprehensive analysis of factors affecting a disease. Family history is an important but not a definitive indicator of inherited predisposition to malignancy and thus studying the germline gene aberrations alongside somatic variants is warranted. The significance of germline predisposition has been increasingly recognized in acute myeloid leukemia and is noted in the latest WHO classification.1,2,3Despite the recent progress in acute lymphoblastic leukemia (ALL) therapies, many adult patients with ALL still do poorly and there is a need for new biomarkers and therapy targets. The aim of our study was to identify and determine the frequency of germline mutations in known ALL genes, to discover new genes associated with ALL predisposition, and to compare the germline genetic background and respective consequences of pediatric and adult high-risk ALL. We examined exome sequencing data from biobanked samples of adult (50) and pediatric (68) patients with high-risk ALL (Finnish Hematological Registry and Biobank - FHRB, and clinical repositories). First, a candidate-gene analysis consisted of 92 genes previously associated with germline predisposition to ALL or syndromes predisposing to ALL. Variants with minor allele frequency of <0.01 in the Genome Aggregation Database were considered. Missense variants were considered significant if ≥2/3 algorithms (CADD, DANN, Revel) classified it as pathogenic. We also reviewed literature, public databases and the American College of Medical Genetics classification (ACMG) in filtering the variants. Clinical characteristics of the patients were retrieved from hospital records and the Finnish Hematological Registry. Second, an unbiased approach was applied to find novel genes predisposing to ALL by checking pathogenic variants in the same gene in at least two (adult/pediatric) patients and filtering by gene ontologies DNA repair, cell cycle, and lymphocyte differentiation; and by COSMIC cancer census genes. In both analyses, only statistically significantly more common variants in our series compared to normal population were included. We also conducted a mutational signature analysis on the samples. Our analysis (Table 1) demonstrates that 8% of adult and 10% pediatric study patients carried a pathogenic or likely pathogenic mutation in their germline in known ALL predisposing genes. All these mutations were at least 30-fold more frequent in our study series compared with allele frequencies in the normal population (p<0.05). Four pediatric patients were identified to suffer from undiagnosed syndromes, which predispose to ALL (Li-Fraumeni and Noonan syndromes). We also found recurring aberrations in new genes with biological relevance to ALL, such as MUTYH and IL21R, potentially associating with ALL predisposition. Final results of the mutational signature analyses are pending. In conclusion, our results emphasize that germline predisposition is not rare among high-risk ALL patients. In addition to pediatric ALL patients, we show contributing germline variants also in adult patients. At least 20% of the adult ALL patients are transplanted and a potential germline basis of the disease should be considered when choosing the donor. Our analysis also reveals new information on the biology of high-risk ALL and may contribute to the future studies seeking for therapy options in this challenging patient category. Despite the anxiety that acknowledging inheritable factors may cause in patients, families, and caretakers, we encourage clinicians to integrate carefully interpreted germline data into patient care. References 1. Wartiovaara-Kautto U et al. Germline alterations in a consecutive series of acute myeloid leukemia. Leukemia. 2018. 2. Arber DA et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016. 3. Tawana K et al. Universal genetic testing for inherited susceptibility in children and adults with myelodysplastic syndrome and acute myeloid leukemia : are we there yet? Leukemia. 2018. Disclosures Porkka: Daiichi Sankyo: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Heckman:Celgene: Research Funding; Novartis: Research Funding; Oncopeptides: Research Funding; Orion Pharma: Research Funding.

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Cheng, Wen-Hsing, Cayetano von Kobbe, Patricia L. Opresko, Kesha M. Fields, Jian Ren, Donald Kufe, and Vilhelm A. Bohr. "Werner Syndrome Protein Phosphorylation by Abl Tyrosine Kinase Regulates Its Activity and Distribution." Molecular and Cellular Biology 23, no. 18 (September 15, 2003): 6385–95. http://dx.doi.org/10.1128/mcb.23.18.6385-6395.2003.

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ABSTRACT The Werner syndrome protein (WRN) is a caretaker of the human genome, and the Abl kinase is a regulator of the DNA damage response. Aberrant DNA repair has been linked to the development of cancer. Here, we have identified a direct binding between WRN and c-Abl in vitro via the N-terminal and central regions of WRN and the Src homology domain 3 of c-Abl. After bleomycin treatment in culture, WRN and c-Abl are dissociated and followed by an Abl kinase-dependent WRN relocalization to the nucleoplasm. WRN is a substrate of c-Abl in vitro and in vivo. WRN is tyrosine phosphorylated either transiently by treatment of HeLa cells with bleomycin or constitutively in cells from chronic myeloid leukemia (CML) patients, and these phosphorylations are prevented by treatment with the Abl kinase inhibitor STI-571. Tyrosine phosphorylation of WRN results in inhibition of both WRN exonuclease and helicase activities. Furthermore, anti-WRN immunoprecipitates from CML cells treated with STI-571 show increased 3′→5′ exonuclease activity. These findings suggest a novel signaling pathway by which c-Abl mediates WRN nuclear localization and catalytic activities in response to DNA damage.

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31

Majera, Dusana, Zdenek Skrott, Katarina Chroma, Joanna Maria Merchut-Maya, Martin Mistrik, and Jiri Bartek. "Targeting the NPL4 Adaptor of p97/VCP Segregase by Disulfiram as an Emerging Cancer Vulnerability Evokes Replication Stress and DNA Damage while Silencing the ATR Pathway." Cells 9, no. 2 (February 18, 2020): 469. http://dx.doi.org/10.3390/cells9020469.

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Research on repurposing the old alcohol-aversion drug disulfiram (DSF) for cancer treatment has identified inhibition of NPL4, an adaptor of the p97/VCP segregase essential for turnover of proteins involved in multiple pathways, as an unsuspected cancer cell vulnerability. While we reported that NPL4 is targeted by the anticancer metabolite of DSF, the bis-diethyldithiocarbamate-copper complex (CuET), the exact, apparently multifaceted mechanism(s) through which the CuET-induced aggregation of NPL4 kills cancer cells remains to be fully elucidated. Given the pronounced sensitivity to CuET in tumor cell lines lacking the genome integrity caretaker proteins BRCA1 and BRCA2, here we investigated the impact of NPL4 targeting by CuET on DNA replication dynamics and DNA damage response pathways in human cancer cell models. Our results show that CuET treatment interferes with DNA replication, slows down replication fork progression and causes accumulation of single-stranded DNA (ssDNA). Such a replication stress (RS) scenario is associated with DNA damage, preferentially in the S phase, and activates the homologous recombination (HR) DNA repair pathway. At the same time, we find that cellular responses to the CuET-triggered RS are seriously impaired due to concomitant malfunction of the ATRIP-ATR-CHK1 signaling pathway that reflects an unorthodox checkpoint silencing mode through ATR (Ataxia telangiectasia and Rad3 related) kinase sequestration within the CuET-evoked NPL4 protein aggregates.

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Abdel-Wahab, Reham, Siraj Mahamed Ali, Mitesh J. Borad, Rachna T. Shroff, Lawrence Kwong, Jean-Nicolas Vauthey, Eugene Jon Koay, et al. "Variations in DNA repair genomic alterations and tumor mutation burden in biliary tract cancer (BTC) subtypes." Journal of Clinical Oncology 36, no. 4_suppl (February 1, 2018): 263. http://dx.doi.org/10.1200/jco.2018.36.4_suppl.263.

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263 Background: DNA repair genomic alterations (GAs) have been identified in 12% of Intrahepatic cholangiocarcinoma (IHCCA), 26% of extrahepatic CCA (EHCCA) and 8% of gallbladder cancer (GBC) patients (pts) ( Cancer 2016;122:3838–3847). Recently, the Cancer Genome Atlas (TCGA) has described more than 20 mutated DNA repair genes, many of which were not previously represented in prior reports. DNA repair GAs including MSI are associated with higher tumor mutational burden (TMB). Our study aim is to identify variations in the frequency of DNA repair GAs in IHCCA, EHCCA, and GBC. Methods: Hybrid capture-based next-generation sequencing of 422 fixed formalin paraffin embedded (FFPE) tissue blocks of BTC including; 270 IHCCA, 60 EHCCA, and 92 GBC was performed. We included 20 DNA repair genes and classified them as "direct" DNA repair genes ( ATM, ATR, BRCA1, BRCA2, FANCA, FANCD2, MLH1, MSH2, MSH6, PALB2, POLD1, POLE, PRKDC, RAD50, SLX4) and "caretaker" genes that induce genomic instability ( BAP1, CDK12, MLL3, TP53, BLM). We calculated TMB on 1.1 Mb of sequenced DNA in 205 tissue specimens [138 IHCCA, 23 EHCCA, and 44 GBC] and classified into three groups; high (TMB-H; ≥ 20 mut/Mb), intermediate (TMB-I; 6-19mut/Mb) and low (TMB-L; < 6mut/Mb). Results: A distinct pattern of DNA repair GAs in each tumor type was detected. (Table 1). DNA repair GAs were more commonly noted in both EHCCA and GB (63%) as compared with IHCAA (45.2%) (p= .002). Direct DNA repair GAs were highest within EHCCA (25%), while indirect DNA GAs were predominant in GBC (59.8%) (p= 0.04 and 0.001, respectively). The frequency of TMB-H and TMB-I differed significantly between BTC subtypes. Pts with EHCCA and GBC had significantly higher TMB-H and TMB-I versus IHCCA. Conclusions: The frequency of DNA repair GA’s is higher in EHCCA and GBC as compared with IHCCA. These results may have implications for clinical trials with DNA repair inhibitors and immune checkpoint blockers. [Table: see text]

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Beetz, Christian, Volha Skrahina, Toni M. Förster, Hanaa Gaber, Jefri J. Paul, Filipa Curado, Arndt Rolfs, et al. "Rapid Large-Scale COVID-19 Testing during Shortages." Diagnostics 10, no. 7 (July 8, 2020): 464. http://dx.doi.org/10.3390/diagnostics10070464.

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The Coronavirus disease 2019 (COVID-19) pandemic caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) has resulted in economic and social lockdowns in most countries all over the globe. Early identification of infected individuals is regarded as one of the most important prerequisites for fighting the pandemic and for returning to a ‘New Normal’. Large-scale testing is therefore crucial, but is facing several challenges including shortage of sample collection tools and of molecular biological reagents, and the need for safe electronic communication of medical reports. We present the successful establishment of a holistic SARS-CoV-2 testing platform that covers proband registration, sample collection and shipment, sample testing, and report issuing. The RT-PCR-based virus detection, being central to the platform, was extensively validated: sensitivity and specificity were defined as 96.8% and 100%, respectively; intra-run and inter-run precision were <3%. A novel type of sample swab and an in-house-developed RNA extraction system were shown to perform as good as commercially available products. The resulting flexibility guarantees independence from the current bottlenecks in SARS-CoV-2 testing. Based on our technology, we offered testing at local, national, and global levels. In the present study, we report the results from approx. 18,000 SARS-CoV-2 tests in almost 10,000 individuals from a low-frequency SARS-CoV-2 pandemic area in a homogenous geographical region in north-eastern Germany for a period of 10 weeks (21 March to 31 May 2020). Among the probands, five SARS-CoV-2 positive cases were identified. Comparative analysis of corresponding virus genomes revealed a diverse origin from three of the five currently recognized SARS-CoV-2 phylogenetic clades. Our study exemplifies how preventive SARS-CoV-2 testing can be set up in a rapid and flexible manner. The application of our test has enabled a safe maintenance/resume of critical local infrastructure, e.g., nursing homes where more than 5000 elderlies and caretakers got tested. The strategy outlined by the present study may serve as a blueprint for the implementation of large-scale preventive SARS-CoV-2 testing elsewhere.

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Farhin, Nitu, Andy Lam, Anjana D. Saxena, and Shaneen Singh. "Abstract 875: Breast cancer bioinformatics: Untangling the roles of nucleolin and BRCA1 in dysregulated DNA repair." Cancer Research 83, no. 7_Supplement (April 4, 2023): 875. http://dx.doi.org/10.1158/1538-7445.am2023-875.

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Abstract Proteins that enable cells to sense and repair DNA damage are essential for maintaining the stability of genomes across cell divisions; dysregulation of these processes is an established hallmark of tumorigenesis. Nucleolin (NCL), a major RNA binding protein (RBP) and a caretaker tumor suppressor protein BRCA1 (the breast & ovarian cancer susceptibility gene) colocalize in breast cancer. Both NCL and BRCA1 have defined roles in homologous recombination (HR) and non-homologous end joining (NHEJ) DNA repair pathways which are often dysregulated in breast cancer. BRCA1, along with a complex molecular network of signaling proteins gets recruited to damaged replication forks to initiate the HR pathway where NCL function is also implicated. However, how NCL collaborates with BRCA1 to orchestrate the complex mechanism of DNA repair under stress conditions remains unknown. To address this gap in knowledge, we have applied in silico approaches to uncover the key players which drive the molecular interactions of NCL and BRCA1 at the damaged sites. We utilized the NIH PPI, IntAct, STRING, BioGRID, GeneMania, PrePPI, and Mentha databases to derive an overlapping interactome. In this study we present a comprehensive interactome analysis and 47 proteins identified that interact with both NCL and BRCA1. As expected, majority of these common interactors participate in DNA damage damage response along with several that are implicated in regulating the gene expression via chromatin remodeling/RNA binding or controlling cell proliferation. We classified this interactome into 5 major categories based on their GO functional annotations: chromatin remodeling, DNA damage, DNA repair, RNA-binding proteins, and cell cycle. Previously, we have successfully used computational approaches to model the RNA-binding domains (RBD) of NCL and delineate the binding interfaces between NCL-RBD and a subset of miRNA that are specifically dysregulated in breast cancer. Using the same strategy, we have modeled the full length NCL to provide a complete structural representation of the protein. Our model fills the gap in missing NCL structural data, especially the unexplored N- and C - termini that may play important roles in NCL protein-protein interactions. Our results provide predicted interaction scenarios between NCL and the subset of the overlapping interactome of NCL and BRCA1, focused on DNA repair mechanisms. These in silico models are critical to understand the protein complexity at the interface of damaged DNA to identify candidates that can be targeted in breast carcinoma. Citation Format: Nitu Farhin, Andy Lam, Anjana D. Saxena, Shaneen Singh. Breast cancer bioinformatics: Untangling the roles of nucleolin and BRCA1 in dysregulated DNA repair [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 875.

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Thakkar, Megha K., Jamie Lee, Stefan Meyer, and Vivian Y. Chang. "RecQ Helicase Somatic Alterations in Cancer." Frontiers in Molecular Biosciences 9 (June 15, 2022). http://dx.doi.org/10.3389/fmolb.2022.887758.

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Named the “caretakers” of the genome, RecQ helicases function in several pathways to maintain genomic stability and repair DNA. This highly conserved family of enzymes consist of five different proteins in humans: RECQL1, BLM, WRN, RECQL4, and RECQL5. Biallelic germline mutations in BLM, WRN, and RECQL4 have been linked to rare cancer-predisposing syndromes. Emerging research has also implicated somatic alterations in RecQ helicases in a variety of cancers, including hematological malignancies, breast cancer, osteosarcoma, amongst others. These alterations in RecQ helicases, particularly overexpression, may lead to increased resistance of cancer cells to conventional chemotherapy. Downregulation of these proteins may allow for increased sensitivity to chemotherapy, and, therefore, may be important therapeutic targets. Here we provide a comprehensive review of our current understanding of the role of RecQ DNA helicases in cancer and discuss the potential therapeutic opportunities in targeting these helicases.

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St. Charles, Jessica L., Phillip T. Brooks, Julia A. Bell, Husnain Ahmed, Mia Van Allen, Shannon D. Manning, and Linda S. Mansfield. "Zoonotic Transmission of Campylobacter jejuni to Caretakers From Sick Pen Calves Carrying a Mixed Population of Strains With and Without Guillain Barré Syndrome-Associated Lipooligosaccharide Loci." Frontiers in Microbiology 13 (April 29, 2022). http://dx.doi.org/10.3389/fmicb.2022.800269.

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Campylobacter jejuni causes foodborne gastroenteritis and may trigger acute autoimmune sequelae including Guillain Barré Syndrome. Onset of neuromuscular paralysis is associated with exposure to C. jejuni lipooligosaccharide (LOS) classes A, B, C, D, and E that mimic and evoke antibodies against gangliosides on myelin and axons of peripheral nerves. Family members managing a Michigan dairy operation reported recurring C. jejuni gastroenteritis. Because dairy cattle are known to shed C. jejuni, we hypothesized that calves in the sick pen were the source of human infections. Fecal samples obtained from twenty-five calves, one dog, and one asymptomatic family member were cultured for Campylobacter. C. jejuni isolates were obtained from thirteen calves and the family member: C. coli from two calves, and C. hyointestinalis from two calves. Some calves had diarrhea; most were clinically normal. Typing of lipooligosaccharide biosynthetic loci showed that eight calf C. jejuni isolates fell into classes A, B, and C. Two calf isolates and the human isolate possessed LOS class E, associated mainly with enteric disease and rarely with Guillain Barré Syndrome. Multi-locus sequence typing, porA and flaA typing, and whole genome comparisons of the thirteen C. jejuni isolates indicated that the three LOS class E strains that included the human isolate were closely related, indicating zoonotic transmission. Whole-genome comparisons revealed that isolates differed in virulence gene content, particularly in loci encoding biosynthesis of surface structures. Family members experienced diarrheal illness repeatedly over 2 years, yet none experienced GBS despite exposure to calves carrying invasive C. jejuni with LOS known to elicit antiganglioside autoantibodies.

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Bhat, Divya S., Eva Malacaria, Ludovica Di Biagi, Mortezaali Razzaghi, Masayoshi Honda, Kathryn F. Hobbs, Sarah R. Hengel, Pietro Pichierri, M. Ashley Spies, and Maria Spies. "Therapeutic disruption of RAD52–ssDNA complexation via novel drug-like inhibitors." NAR Cancer 5, no. 2 (March 11, 2023). http://dx.doi.org/10.1093/narcan/zcad018.

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Abstract RAD52 protein is a coveted target for anticancer drug discovery. Similar to poly-ADP-ribose polymerase (PARP) inhibitors, pharmacological inhibition of RAD52 is synthetically lethal with defects in genome caretakers BRCA1 and BRCA2 (∼25% of breast and ovarian cancers). Emerging structure activity relationships for RAD52 are complex, making it challenging to transform previously identified disruptors of the RAD52–ssDNA interaction into drug-like leads using traditional medicinal chemistry approaches. Using pharmacophoric informatics on the RAD52 complexation by epigallocatechin (EGC), and the Enamine in silico REAL database, we identified six distinct chemical scaffolds that occupy the same physical space on RAD52 as EGC. All six were RAD52 inhibitors (IC50 ∼23–1200 μM) with two of the compounds (Z56 and Z99) selectively killing BRCA-mutant cells and inhibiting cellular activities of RAD52 at micromolar inhibitor concentrations. While Z56 had no effect on the ssDNA-binding protein RPA and was toxic to BRCA-mutant cells only, Z99 inhibited both proteins and displayed toxicity towards BRCA-complemented cells. Optimization of the Z99 scaffold resulted in a set of more powerful and selective inhibitors (IC50 ∼1.3–8 μM), which were only toxic to BRCA-mutant cells. RAD52 complexation by Z56, Z99 and its more specific derivatives provide a roadmap for next generation of cancer therapeutics.

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Kincaid, Rodney P., Yating Chen, Jennifer E. Cox, Axel Rethwilm, and Christopher S. Sullivan. "Noncanonical MicroRNA (miRNA) Biogenesis Gives Rise to Retroviral Mimics of Lymphoproliferative and Immunosuppressive Host miRNAs." mBio 5, no. 2 (April 8, 2014). http://dx.doi.org/10.1128/mbio.00074-14.

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ABSTRACTMicroRNAs (miRNAs) play regulatory roles in diverse processes in both eukaryotic hosts and their viruses, yet fundamental questions remain about which viruses code for miRNAs and the functions that they serve. Simian foamy viruses (SFVs) of Old World monkeys and apes can zoonotically infect humans and, by ill-defined mechanisms, take up lifelong infections in their hosts. Here, we report that SFVs encode multiple miRNAs via a noncanonical mode of biogenesis. The primary SFV miRNA transcripts (pri-miRNAs) are transcribed by RNA polymerase III (RNAP III) and take multiple forms, including some that are cleaved by Drosha. However, these miRNAs are generated in a context-dependent fashion, as longer RNAP II transcripts spanning this region are resistant to Drosha cleavage. This suggests that the virus may avoid any fitness penalty that could be associated with viral genome/transcript cleavage. Two SFV miRNAs share sequence similarity and functionality with notable host miRNAs, the lymphoproliferative miRNA miR-155 and the innate immunity suppressor miR-132. These results have important implications regarding foamy virus biology, viral miRNAs, and the development of retroviral-based vectors.IMPORTANCEFundamental questions remain about which viruses encode miRNAs and their associated functions. Currently, few natural viruses with RNA genomes have been reported to encode miRNAs. Simian foamy viruses are retroviruses that are prevalent in nonhuman host populations, and some can zoonotically infect humans who hunt primates or work as animal caretakers. We identify a cluster of miRNAs encoded by SFV. Characterization of these miRNAs reveals evolutionarily conserved, unconventional mechanisms to generate small RNAs. Several SFV miRNAs share sequence similarity and functionality with host miRNAs, including the oncogenic miRNA miR-155 and innate immunity suppressor miR-132. Strikingly, unrelated herpesviruses also tap into one or both of these same regulatory pathways, implying relevance to a broad range of viruses. These findings provide new insights with respect to foamy virus biology and vectorology.

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Koomar, Tanner, Taylor R. Thomas, Natalie R. Pottschmidt, Michael Lutter, and Jacob J. Michaelson. "Estimating the Prevalence and Genetic Risk Mechanisms of ARFID in a Large Autism Cohort." Frontiers in Psychiatry 12 (June 9, 2021). http://dx.doi.org/10.3389/fpsyt.2021.668297.

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This study is the first genetically-informed investigation of avoidant/restrictive food intake disorder (ARFID), an eating disorder that profoundly impacts quality of life for those affected. ARFID is highly comorbid with autism, and we provide the first estimate of its prevalence in a large and phenotypically diverse autism cohort (a subsample of the SPARK study, N = 5,157 probands). This estimate, 21% (at a balanced accuracy 80%), is at the upper end of previous estimates from studies based on clinical samples, suggesting under-diagnosis and potentially lack of awareness among caretakers and clinicians. Although some studies suggest a decrease of disordered eating symptoms by age 6, our estimates indicate that up to 17% (at a balanced accuracy 87%) of parents of autistic children are also at heightened risk for ARFID, suggesting a lifelong risk for disordered eating. We were also able to provide the first estimates of narrow-sense heritability (h2) for ARFID risk, at 0.45. Genome-wide association revealed a single hit near ZSWIM6, a gene previously implicated in neurodevelopmental conditions. While, the current sample was not well-powered for GWAS, effect size and heritability estimates allowed us to project the sample sizes necessary to more robustly discover ARFID-linked loci via common variants. Further genetic analysis using polygenic risk scores (PRS) affirmed genetic links to autism as well as neuroticism and metabolic syndrome.

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Muniesa-Vargas, Alba, Arjan F. Theil, Cristina Ribeiro-Silva, Wim Vermeulen, and Hannes Lans. "XPG: a multitasking genome caretaker." Cellular and Molecular Life Sciences 79, no. 3 (March 2022). http://dx.doi.org/10.1007/s00018-022-04194-5.

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AbstractThe XPG/ERCC5 endonuclease was originally identified as the causative gene for Xeroderma Pigmentosum complementation group G. Ever since its discovery, in depth biochemical, structural and cell biological studies have provided detailed mechanistic insight into its function in excising DNA damage in nucleotide excision repair, together with the ERCC1–XPF endonuclease. In recent years, it has become evident that XPG has additional important roles in genome maintenance that are independent of its function in NER, as XPG has been implicated in protecting replication forks by promoting homologous recombination as well as in resolving R-loops. Here, we provide an overview of the multitasking of XPG in genome maintenance, by describing in detail how its activity in NER is regulated and the evidence that points to important functions outside of NER. Furthermore, we present the various disease phenotypes associated with inherited XPG deficiency and discuss current ideas on how XPG deficiency leads to these different types of disease.

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Yu, Veronica. "Caretaker Brca1: keeping the genome in the straight and narrow." Breast Cancer Research 2, no. 2 (April 2000). http://dx.doi.org/10.1186/bcr37.

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Knoll, Alexander, Susan Schröpfer, and Holger Puchta. "The RTR complex as caretaker of genome stability and its unique meiotic function in plants." Frontiers in Plant Science 5 (2014). http://dx.doi.org/10.3389/fpls.2014.00033.

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Kermasson, Laëtitia, Dmitri Churikov, Aya Awad, Riham Smoom, Elodie Lainey, Fabien Touzot, Séverine Audebert-Bellanger, et al. "Inherited human Apollo deficiency causes severe bone marrow failure and developmental defects." Blood, January 10, 2022. http://dx.doi.org/10.1182/blood.2021010791.

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Inherited bone marrow failure syndromes (IBMFS) represent a group of disorders typified by impaired production of one or several blood cell types. The telomere biology disorders dyskeratosis congenita (DC) and its severe variant Høyeraal-Hreidarsson (HH) syndrome are rare IBMFS characterized by bone marrow failure, developmental defects, and various premature aging complications associated with critically short telomeres. Here we identified biallelic variants in the gene encoding the 5'-to-3' DNA exonuclease Apollo/SNM1B in three unrelated patients presenting with a DC/HH phenotype consisting of early onset hypocellular bone marrow failure, B and NK lymphopenia, developmental anomalies, microcephaly and/or intrauterine growth retardation. All three patients carry a homozygous or compound heterozygous (in combination with a null-allele) missense variant affecting the same residue L142 (L142F or L142S) located in the catalytic domain of Apollo. Apollo-deficient cells from patients exhibited spontaneous chromosome instability and impaired DNA repair that was complemented by CRISPR/Cas9-mediated gene correction. Furthermore, patients' cells showed signs of telomere fragility that were however not associated with global reduction of telomere length. Unlike patients' cells, human Apollo KO HT1080-cell lines showed strong telomere dysfunction accompanied by excessive telomere shortening, suggesting that the L142S and L142F Apollo variants are hypomorphic. Collectively, these findings define human Apollo as a genome caretaker and identify biallelic Apollo variants as a genetic cause of a hitherto unrecognized severe IBMFS combining clinical hallmarks of DC/HH with normal telomere length.

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Bellon, Marcia, Izabela Bialuk, Veronica Galli, Xue-Tao Bai, Lourdes Farre, Achilea Bittencourt, Ambroise Marçais, et al. "Germinal epimutation of Fragile Histidine Triad (FHIT) gene is associated with progression to acute and chronic adult T-cell leukemia diseases." Molecular Cancer 20, no. 1 (June 6, 2021). http://dx.doi.org/10.1186/s12943-021-01370-2.

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Abstract Background Human T cell Leukemia virus type 1 (HTLV-I) is etiologically linked to adult T cell leukemia/lymphoma (ATL) and an inflammatory neurodegenerative disease called HTLV-I-associated myelopathy or tropical spastic paraparesis (HAM/TSP). The exact genetic or epigenetic events and/or environmental factors that influence the development of ATL, or HAM/TSP diseases are largely unknown. The tumor suppressor gene, Fragile Histidine Triad Diadenosine Triphosphatase (FHIT), is frequently lost in cancer through epigenetic modifications and/or deletion. FHIT is a tumor suppressor acting as genome caretaker by regulating cellular DNA repair. Indeed, FHIT loss leads to replicative stress and accumulation of double DNA strand breaks. Therefore, loss of FHIT expression plays a key role in cellular transformation. Methods Here, we studied over 400 samples from HTLV-I-infected individuals with ATL, TSP/HAM, or asymptomatic carriers (AC) for FHIT loss and expression. We examined the epigenetic status of FHIT through methylation specific PCR and bisulfite sequencing; and correlated these results to FHIT expression in patient samples. Results We found that epigenetic alteration of FHIT is specifically found in chronic and acute ATL but is absent in asymptomatic HTLV-I carriers and TSP/HAM patients’ samples. Furthermore, the extent of FHIT methylation in ATL patients was quantitatively comparable in virus-infected and virus non-infected cells. We also found that longitudinal HTLV-I carriers that progressed to smoldering ATL and descendants of ATL patients harbor FHIT methylation. Conclusions These results suggest that germinal epigenetic mutation of FHIT represents a preexisting mark predisposing to the development of ATL diseases. These findings have important clinical implications as patients with acute ATL are rarely cured. Our study suggests an alternative strategy to the current “wait and see approach” in that early screening of HTLV-I-infected individuals for germinal epimutation of FHIT and early treatment may offer significant clinical benefits.

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