Journal articles: 'Paralogues de Rad51'

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Tarsounas, Madalena, Adelina A. Davies, and Stephen C. West. "RAD51 localization and activation following DNA damage." Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences 359, no. 1441 (January 29, 2004): 87–93. http://dx.doi.org/10.1098/rstb.2003.1368.

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The efficient repair of double–strand breaks in DNA is critical for the maintenance of genome stability. In response to ionizing radiation and other DNA–damaging agents, the RAD51 protein, which is essential for homologous recombination, relocalizes within the nucleus to form distinct foci that can be visualized by microscopy and are thought to represent sites where repair reactions take place. The formation of RAD51 foci in response to DNA damage is dependent upon BRCA2 and a series of proteins known as the RAD51 paralogues (RAD51B, RAD51C, RAD51D, XRCC2 and XRCC3), indicating that the components present within foci assemble in a carefully orchestrated and ordered manner. By contrast, RAD51 foci that form spontaneously as cells undergo DNA replication at S phase occur without the need for BRCA2 or the RAD51 paralogues. It is known that BRCA2 interacts directly with RAD51 through a series of degenerative motifs known as the BRC repeats. These interactions modulate the ability of RAD51 to bind DNA. Taken together, these observations indicate that BRCA2 plays a critical role in controlling the actions of RAD51 at both the microscopic (focus formation) and molecular (DNA binding) level.

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Godin, Stephen K., Meghan R. Sullivan, and Kara A. Bernstein. "Novel insights into RAD51 activity and regulation during homologous recombination and DNA replication." Biochemistry and Cell Biology 94, no. 5 (October 2016): 407–18. http://dx.doi.org/10.1139/bcb-2016-0012.

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In this review we focus on new insights that challenge our understanding of homologous recombination (HR) and Rad51 regulation. Recent advances using high-resolution microscopy and single molecule techniques have broadened our knowledge of Rad51 filament formation and strand invasion at double-strand break (DSB) sites and at replication forks, which are one of most physiologically relevant forms of HR from yeast to humans. Rad51 filament formation and strand invasion is regulated by many mediator proteins such as the Rad51 paralogues and the Shu complex, consisting of a Shu2/SWS1 family member and additional Rad51 paralogues. Importantly, a novel RAD51 paralogue was discovered in Caenorhabditis elegans, and its in vitro characterization has demonstrated a new function for the worm RAD51 paralogues during HR. Conservation of the human RAD51 paralogues function during HR and repair of replicative damage demonstrate how the RAD51 mediators play a critical role in human health and genomic integrity. Together, these new findings provide a framework for understanding RAD51 and its mediators in DNA repair during multiple cellular contexts.

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Liu, Jie, Ludovic Renault, Xavier Veaute, Francis Fabre, Henning Stahlberg, and Wolf-Dietrich Heyer. "Rad51 paralogues Rad55–Rad57 balance the antirecombinase Srs2 in Rad51 filament formation." Nature 479, no. 7372 (October 23, 2011): 245–48. http://dx.doi.org/10.1038/nature10522.

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Angelis, Karel J., Lenka Záveská Drábková, Radka Vágnerová, and Marcela Holá. "RAD51 and RAD51B Play Diverse Roles in the Repair of DNA Double Strand Breaks in Physcomitrium patens." Genes 14, no. 2 (January 24, 2023): 305. http://dx.doi.org/10.3390/genes14020305.

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RAD51 is involved in finding and invading homologous DNA sequences for accurate homologous recombination (HR). Its paralogs have evolved to regulate and promote RAD51 functions. The efficient gene targeting and high HR rates are unique in plants only in the moss Physcomitrium patens (P. patens). In addition to two functionally equivalent RAD51 genes (RAD1-1 and RAD51-2), other RAD51 paralogues were also identified in P. patens. For elucidation of RAD51’s involvement during DSB repair, two knockout lines were constructed, one mutated in both RAD51 genes (Pprad51-1-2) and the second with mutated RAD51B gene (Pprad51B). Both lines are equally hypersensitive to bleomycin, in contrast to their very different DSB repair efficiency. Whereas DSB repair in Pprad51-1-2 is even faster than in WT, in Pprad51B, it is slow, particularly during the second phase of repair kinetic. We interpret these results as PpRAD51-1 and -2 being true functional homologs of ancestral RAD51 involved in the homology search during HR. Absence of RAD51 redirects DSB repair to the fast NHEJ pathway and leads to a reduced 5S and 18S rDNA copy number. The exact role of the RAD51B paralog remains unclear, though it is important in damage recognition and orchestrating HR response.

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Khoo, Kelvin H. P., Hayley R. Jolly, and Jason A. Able. "The RAD51 gene family in bread wheat is highly conserved across eukaryotes, with RAD51A upregulated during early meiosis." Functional Plant Biology 35, no. 12 (2008): 1267. http://dx.doi.org/10.1071/fp08203.

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The RADiation sensitive protein 51 (RAD51) recombinase is a eukaryotic homologue of the bacterial Recombinase A (RecA). It is required for homologous recombination of DNA during meiosis where it plays a role in processes such as homology searching and strand invasion. RAD51 is well conserved in eukaryotes with as many as four paralogues identified in vertebrates and some higher plants. Here we report the isolation and preliminary characterisation of four RAD51 gene family members in hexaploid (bread) wheat (Triticum aestivum L.). RAD51A1, RAD51A2 and RAD51D were located on chromosome group 7, and RAD51C was on chromosome group 2. Q-PCR gene expression profiling revealed that RAD51A1 was upregulated during meiosis with lower expression levels seen in mitotic tissue, and bioinformatics analysis demonstrated the evolutionary linkages of this gene family to other eukaryotic RAD51 sequences. Western blot analysis of heterologously expressed RAD51 from bread wheat has shown that it is detectable using anti-human RAD51 antibodies and that molecular modelling of the same protein revealed structural conservation when compared with yeast, human, Arabidopsis and maize RAD51A orthologues. This report has widened the knowledge base of this important protein family in plants, and highlighted the high level of structural conservation among RAD51 proteins from various species.

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Pohl, Thomas J., and Jac A. Nickoloff. "Rad51-Independent Interchromosomal Double-Strand Break Repair by Gene Conversion Requires Rad52 but Not Rad55, Rad57, or Dmc1." Molecular and Cellular Biology 28, no. 3 (November 26, 2007): 897–906. http://dx.doi.org/10.1128/mcb.00524-07.

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ABSTRACT Homologous recombination (HR) is critical for DNA double-strand break (DSB) repair and genome stabilization. In yeast, HR is catalyzed by the Rad51 strand transferase and its “mediators,” including the Rad52 single-strand DNA-annealing protein, two Rad51 paralogs (Rad55 and Rad57), and Rad54. A Rad51 homolog, Dmc1, is important for meiotic HR. In wild-type cells, most DSB repair results in gene conversion, a conservative HR outcome. Because Rad51 plays a central role in the homology search and strand invasion steps, DSBs either are not repaired or are repaired by nonconservative single-strand annealing or break-induced replication mechanisms in rad51Δ mutants. Although DSB repair by gene conversion in the absence of Rad51 has been reported for ectopic HR events (e.g., inverted repeats or between plasmids), Rad51 has been thought to be essential for DSB repair by conservative interchromosomal (allelic) gene conversion. Here, we demonstrate that DSBs stimulate gene conversion between homologous chromosomes (allelic conversion) by >30-fold in a rad51Δ mutant. We show that Rad51-independent allelic conversion and break-induced replication occur independently of Rad55, Rad57, and Dmc1 but require Rad52. Unlike DSB-induced events, spontaneous allelic conversion was detected in both rad51Δ and rad52Δ mutants, but not in a rad51Δ rad52Δ double mutant. The frequencies of crossovers associated with DSB-induced gene conversion were similar in the wild type and the rad51Δ mutant, but discontinuous conversion tracts were fivefold more frequent and tract lengths were more widely distributed in the rad51Δ mutant, indicating that heteroduplex DNA has an altered structure, or is processed differently, in the absence of Rad51.

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Godin, Stephen, Adam Wier, Faiz Kabbinavar, Dominique S. Bratton-Palmer, Harshad Ghodke, Bennett Van Houten, Andrew P. VanDemark, and Kara A. Bernstein. "The Shu complex interacts with Rad51 through the Rad51 paralogues Rad55–Rad57 to mediate error-free recombination." Nucleic Acids Research 41, no. 8 (March 4, 2013): 4525–34. http://dx.doi.org/10.1093/nar/gkt138.

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Badie, Sophie, Chunyan Liao, Maria Thanasoula, Paul Barber, Mark A. Hill, and Madalena Tarsounas. "RAD51C facilitates checkpoint signaling by promoting CHK2 phosphorylation." Journal of Cell Biology 185, no. 4 (May 18, 2009): 587–600. http://dx.doi.org/10.1083/jcb.200811079.

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The RAD51 paralogues act in the homologous recombination (HR) pathway of DNA repair. Human RAD51C (hRAD51C) participates in branch migration and Holliday junction resolution and thus is important for processing HR intermediates late in the DNA repair process. Evidence for early involvement of RAD51 during DNA repair also exists, but its function in this context is not understood. In this study, we demonstrate that RAD51C accumulates at DNA damage sites concomitantly with the RAD51 recombinase and is retained after RAD51 disassembly, which is consistent with both an early and a late function for RAD51C. RAD51C recruitment depends on ataxia telangiectasia mutated, NBS1, and replication protein A, indicating it functions after DNA end resection but before RAD51 assembly. Furthermore, we find that RAD51C is required for activation of the checkpoint kinase CHK2 and cell cycle arrest in response to DNA damage. This suggests that hRAD51C contributes to the protection of genome integrity by transducing DNA damage signals in addition to engaging the HR machinery.

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Yang, Yongjia, Jihong Guo, Lei Dai, Yimin Zhu, Hao Hu, Lihong Tan, Weijian Chen, et al. "XRCC2 mutation causes meiotic arrest, azoospermia and infertility." Journal of Medical Genetics 55, no. 9 (July 24, 2018): 628–36. http://dx.doi.org/10.1136/jmedgenet-2017-105145.

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BackgroundMeiotic homologous recombination (HR) plays an essential role in gametogenesis. In most eukaryotes, meiotic HR is mediated by two recombinase systems: ubiquitous RAD51 and meiosis-specific DMC1. In the RAD51-mediated HR system, RAD51 and five RAD51 paralogues are essential for normal RAD51 function, but the role of RAD51 in human meiosis is unclear. The knockout of Rad51 or any Rad51 paralogue in mice exhibits embryonic lethality. We investigated a family with meiotic arrest, azoospermia and infertility but without other abnormalities.MethodsHomozygosity mapping and whole-exome sequencing were performed in a consanguineous family. An animal model carrying a related mutation was created by using a CRISPR/Cas9 system.ResultsWe identified a 1 bp homozygous substitution (c.41T>C/p.Leu14Pro) on a RAD51 paralogue, namely, XRCC2, in the consanguineous family. We did not detect any XRCC2 recessive mutation in a cohort of 127 males with non-obstructive-azoospermia. Knockin mice with Xrcc2-c.T41C/p.Leu14Pro mutation were generated successfully by the CRISPR/Cas9 method. The homozygotes survived and exhibited meiotic arrest, azoospermia, premature ovarian failure and infertility.ConclusionA XRCC2 recessive mutation causing meiotic arrest and infertility in humans was duplicated with knockin mice. Our results revealed a new Mendelian hereditary entity and provided an experimental model of RAD51-HR gene defect in mammalian meiosis.

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Roy, Upasana, and Eric C. Greene. "The Role of the Rad55–Rad57 Complex in DNA Repair." Genes 12, no. 9 (September 8, 2021): 1390. http://dx.doi.org/10.3390/genes12091390.

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Homologous recombination (HR) is a mechanism conserved from bacteria to humans essential for the accurate repair of DNA double-stranded breaks, and maintenance of genome integrity. In eukaryotes, the key DNA transactions in HR are catalyzed by the Rad51 recombinase, assisted by a host of regulatory factors including mediators such as Rad52 and Rad51 paralogs. Rad51 paralogs play a crucial role in regulating proper levels of HR, and mutations in the human counterparts have been associated with diseases such as cancer and Fanconi Anemia. In this review, we focus on the Saccharomyces cerevisiae Rad51 paralog complex Rad55–Rad57, which has served as a model for understanding the conserved role of Rad51 paralogs in higher eukaryotes. Here, we discuss the results from early genetic studies, biochemical assays, and new single-molecule observations that have together contributed to our current understanding of the molecular role of Rad55–Rad57 in HR.

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Tsukamoto, Mariko, Kentaro Yamashita, Toshiko Miyazaki, Miki Shinohara, and Akira Shinohara. "The N-Terminal DNA-Binding Domain of Rad52 PromotesRAD51-Independent Recombination inSaccharomyces cerevisiae." Genetics 165, no. 4 (December 1, 2003): 1703–15. http://dx.doi.org/10.1093/genetics/165.4.1703.

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AbstractIn Saccharomyces cerevisiae, the Rad52 protein plays a role in both RAD51-dependent and RAD51-independent recombination pathways. We characterized a rad52 mutant, rad52-329, which lacks the C-terminal Rad51-interacting domain, and studied its role in RAD51-independent recombination. The rad52-329 mutant is completely defective in mating-type switching, but partially proficient in recombination between inverted repeats. We also analyzed the effect of the rad52-329 mutant on telomere recombination. Yeast cells lacking telomerase maintain telomere length by recombination. The rad52-329 mutant is deficient in RAD51-dependent telomere recombination, but is proficient in RAD51-independent telomere recombination. In addition, we examined the roles of other recombination genes in the telomere recombination. The RAD51-independent recombination in the rad52-329 mutant is promoted by a paralogue of Rad52, Rad59. All components of the Rad50-Mre11-Xrs2 complex are also important, but not essential, for RAD51-independent telomere recombination. Interestingly, RAD51 inhibits the RAD51-independent, RAD52-dependent telomere recombination. These findings indicate that Rad52 itself, and more precisely its N-terminal DNA-binding domain, promote an essential reaction in recombination in the absence of RAD51.

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Sullivan, Meghan R., and Kara A. Bernstein. "RAD-ical New Insights into RAD51 Regulation." Genes 9, no. 12 (December 13, 2018): 629. http://dx.doi.org/10.3390/genes9120629.

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The accurate repair of DNA is critical for genome stability and cancer prevention. DNA double-strand breaks are one of the most toxic lesions; however, they can be repaired using homologous recombination. Homologous recombination is a high-fidelity DNA repair pathway that uses a homologous template for repair. One central HR step is RAD51 nucleoprotein filament formation on the single-stranded DNA ends, which is a step required for the homology search and strand invasion steps of HR. RAD51 filament formation is tightly controlled by many positive and negative regulators, which are collectively termed the RAD51 mediators. The RAD51 mediators function to nucleate, elongate, stabilize, and disassemble RAD51 during repair. In model organisms, RAD51 paralogs are RAD51 mediator proteins that structurally resemble RAD51 and promote its HR activity. New functions for the RAD51 paralogs during replication and in RAD51 filament flexibility have recently been uncovered. Mutations in the human RAD51 paralogs (RAD51B, RAD51C, RAD51D, XRCC2, XRCC3, and SWSAP1) are found in a subset of breast and ovarian cancers. Despite their discovery three decades ago, few advances have been made in understanding the function of the human RAD51 paralogs. Here, we discuss the current perspective on the in vivo and in vitro function of the RAD51 paralogs, and their relationship with cancer in vertebrate models.

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Nagaraju, Ganesh, Andrea Hartlerode, Amy Kwok, Gurushankar Chandramouly, and Ralph Scully. "XRCC2 and XRCC3 Regulate the Balance between Short- and Long-Tract Gene Conversions between Sister Chromatids." Molecular and Cellular Biology 29, no. 15 (May 26, 2009): 4283–94. http://dx.doi.org/10.1128/mcb.01406-08.

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ABSTRACT Sister chromatid recombination (SCR) is a potentially error-free pathway for the repair of DNA lesions associated with replication and is thought to be important for suppressing genomic instability. The mechanisms regulating the initiation and termination of SCR in mammalian cells are poorly understood. Previous work has implicated all the Rad51 paralogs in the initiation of gene conversion and the Rad51C/XRCC3 complex in its termination. Here, we show that hamster cells deficient in the Rad51 paralog XRCC2, a component of the Rad51B/Rad51C/Rad51D/XRCC2 complex, reveal a bias in favor of long-tract gene conversion (LTGC) during SCR. This defect is corrected by expression of wild-type XRCC2 and also by XRCC2 mutants defective in ATP binding and hydrolysis. In contrast, XRCC3-mediated homologous recombination and suppression of LTGC are dependent on ATP binding and hydrolysis. These results reveal an unexpectedly general role for Rad51 paralogs in the control of the termination of gene conversion between sister chromatids.

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Bernstein, Kara A., Robert J. D. Reid, Ivana Sunjevaric, Kimberly Demuth, Rebecca C. Burgess, and Rodney Rothstein. "The Shu complex, which contains Rad51 paralogues, promotes DNA repair through inhibition of the Srs2 anti-recombinase." Molecular Biology of the Cell 22, no. 9 (May 2011): 1599–607. http://dx.doi.org/10.1091/mbc.e10-08-0691.

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The Shu complex, which contains RAD51 paralogues, is involved in the decision between homologous recombination and error-prone repair. We discovered a link to ribosomal DNA (rDNA) recombination when we found an interaction between one member of the Shu complex, SHU1, and UAF30, a component of the upstream activating factor complex (UAF), which regulates rDNA transcription. In the absence of Uaf30, rDNA copy number increases, and this increase depends on several functional subunits of the Shu complex. Furthermore, in the absence of Uaf30, we find that Shu1 and Srs2, an anti-recombinase DNA helicase with which the Shu complex physically interacts, act in the same pathway regulating rDNA recombination. In addition, Shu1 modulates Srs2 recruitment to both induced and spontaneous foci correlating with a decrease in Rad51 foci, demonstrating that the Shu complex is an important regulator of Srs2 activity. Last, we show that Shu1 regulation of Srs2 to double-strand breaks is not restricted to the rDNA, indicating a more general function for the Shu complex in the regulation of Srs2. We propose that the Shu complex shifts the balance of repair toward Rad51 filament stabilization by inhibiting the disassembly reaction of Srs2.

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Dobson, Rachel, Christopher Stockdale, Craig Lapsley, Jonathan Wilkes, and Richard McCulloch. "Interactions among Trypanosoma brucei RAD51 paralogues in DNA repair and antigenic variation." Molecular Microbiology 81, no. 2 (May 26, 2011): 434–56. http://dx.doi.org/10.1111/j.1365-2958.2011.07703.x.

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Hatanaka, Atsushi, Mitsuyoshi Yamazoe, Julian E. Sale, Minoru Takata, Kazuhiko Yamamoto, Hiroyuki Kitao, Eiichiro Sonoda, Koji Kikuchi, Yasukazu Yonetani, and Shunichi Takeda. "Similar Effects of Brca2 Truncation and Rad51 Paralog Deficiency on Immunoglobulin V Gene Diversification in DT40 Cells Support an Early Role for Rad51 Paralogs in Homologous Recombination." Molecular and Cellular Biology 25, no. 3 (February 1, 2005): 1124–34. http://dx.doi.org/10.1128/mcb.25.3.1124-1134.2005.

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ABSTRACT BRCA2 is a tumor suppressor gene that is linked to hereditary breast and ovarian cancer. Although the Brca2 protein participates in homologous DNA recombination (HR), its precise role remains unclear. From chicken DT40 cells, we generated BRCA2 gene-deficient cells which harbor a truncation at the 3′ end of the BRC3 repeat (brca2tr). Comparison of the characteristics of brca2tr cells with those of other HR-deficient DT40 clones revealed marked similarities with rad51 paralog mutants (rad51b, rad51c, rad51d, xrcc2, or xrcc3 cells). The phenotypic similarities include a shift from HR-mediated diversification to single-nucleotide substitutions in the immunoglobulin variable gene segment and the partial reversion of this shift by overexpression of Rad51. Although recent evidence supports at least Xrcc3 and Rad51C playing a role late in HR, our data suggest that Brca2 and the Rad51 paralogs may also contribute to HR at the same early step, with their loss resulting in the stimulation of an alternative, error-prone repair pathway.

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Simo Cheyou, Estelle, Jacopo Boni, Jonathan Boulais, Edgar Pinedo-Carpio, Abba Malina, Dana Sherill-Rofe, Vincent M. Luo, et al. "Systematic proximal mapping of the classical RAD51 paralogs unravel functionally and clinically relevant interactors for genome stability." PLOS Genetics 18, no. 11 (November 14, 2022): e1010495. http://dx.doi.org/10.1371/journal.pgen.1010495.

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Homologous recombination (HR) plays an essential role in the maintenance of genome stability by promoting the repair of cytotoxic DNA double strand breaks (DSBs). More recently, the HR pathway has emerged as a core component of the response to replication stress, in part by protecting stalled replication forks from nucleolytic degradation. In that regard, the mammalian RAD51 paralogs (RAD51B, RAD51C, RAD51D, XRCC2, and XRCC3) have been involved in both HR-mediated DNA repair and collapsed replication fork resolution. Still, it remains largely obscure how they participate in both processes, thereby maintaining genome stability and preventing cancer development. To gain better insight into their contribution in cellulo, we mapped the proximal interactome of the classical RAD51 paralogs using the BioID approach. Aside from identifying the well-established BCDX2 and CX3 sub-complexes, the spliceosome machinery emerged as an integral component of our proximal mapping, suggesting a crosstalk between this pathway and the RAD51 paralogs. Furthermore, we noticed that factors involved RNA metabolic pathways are significantly modulated within the BioID of the classical RAD51 paralogs upon exposure to hydroxyurea (HU), pointing towards a direct contribution of RNA processing during replication stress. Importantly, several members of these pathways have prognostic potential in breast cancer (BC), where their RNA expression correlates with poorer patient outcome. Collectively, this study uncovers novel functionally relevant partners of the different RAD51 paralogs in the maintenance of genome stability that could be used as biomarkers for the prognosis of BC.

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Maloisel, Laurent, Emilie Ma, Jamie Phipps, Alice Deshayes, Stefano Mattarocci, Stéphane Marcand, Karine Dubrana, and Eric Coïc. "Rad51 filaments assembled in the absence of the complex formed by the Rad51 paralogs Rad55 and Rad57 are outcompeted by translesion DNA polymerases on UV-induced ssDNA gaps." PLOS Genetics 19, no. 2 (February 7, 2023): e1010639. http://dx.doi.org/10.1371/journal.pgen.1010639.

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The bypass of DNA lesions that block replicative polymerases during DNA replication relies on DNA damage tolerance pathways. The error-prone translesion synthesis (TLS) pathway depends on specialized DNA polymerases that incorporate nucleotides in front of base lesions, potentially inducing mutagenesis. Two error-free pathways can bypass the lesions: the template switching pathway, which uses the sister chromatid as a template, and the homologous recombination pathway (HR), which also can use the homologous chromosome as template. The balance between error-prone and error-free pathways controls the mutagenesis level. Therefore, it is crucial to precisely characterize factors that influence the pathway choice to better understand genetic stability at replication forks. In yeast, the complex formed by the Rad51 paralogs Rad55 and Rad57 promotes HR and template-switching at stalled replication forks. At DNA double-strand breaks (DSBs), this complex promotes Rad51 filament formation and stability, notably by counteracting the Srs2 anti-recombinase. To explore the role of the Rad55-Rad57 complex in error-free pathways, we monitored the genetic interactions between Rad55-Rad57, the translesion polymerases Polζ or Polη, and Srs2 following UV radiation that induces mostly single-strand DNA gaps. We found that the Rad55-Rad57 complex was involved in three ways. First, it protects Rad51 filaments from Srs2, as it does at DSBs. Second, it promotes Rad51 filament stability independently of Srs2. Finally, we observed that UV-induced HR is almost abolished in Rad55-Rad57 deficient cells, and is partially restored upon Polζ or Polη depletion. Hence, we propose that the Rad55-Rad57 complex is essential to promote Rad51 filament stability on single-strand DNA gaps, notably to counteract the error-prone TLS polymerases and mutagenesis.

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Arakawa, Hiroshi, and Jean-Marie Buerstedde. "Activation-induced cytidine deaminase-mediated hypermutation in the DT40 cell line." Philosophical Transactions of the Royal Society B: Biological Sciences 364, no. 1517 (November 13, 2008): 639–44. http://dx.doi.org/10.1098/rstb.2008.0202.

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Depending on the species and the developmental stage of B cells, activation-induced cytidine deaminase (AID) triggers immunoglobulin ( Ig ) gene diversification by gene conversion, hypermutation or switch recombination. The bursal B cell line DT40 usually diversifies its rearranged Ig light chain ( IgL ) gene by gene conversion, but disruption of the RAD51 gene paralogues or deletion of the ψV conversion donors induces hypermutation. Although not all aspects of somatic hypermutation can be studied in DT40, the compact size of the chicken IgL locus and the ability to modify the genome by targeted integration are powerful experimental advantages. We review here how the studies in DT40 contributed to understanding how AID initiates Ig gene diversification and how AID-induced uracils are subsequently processed by uracil DNA glycosylase, proliferating cell nuclear antigens and error-prone polymerases. We also discuss the on-going research on the Ig locus specificity of hypermutation and the possibility of using hypermutation for the artificial evolution of proteins and regulatory sequences in DT40.

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Daboussi, Fayza, John Thacker, and Bernard S. Lopez. "Genetic interactions between RAD51 and its paralogues for centrosome fragmentation and ploidy control, independently of the sensitivity to genotoxic stresses." Oncogene 24, no. 22 (March 21, 2005): 3691–96. http://dx.doi.org/10.1038/sj.onc.1208438.

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Wesoly, Joanna, Sheba Agarwal, Stefan Sigurdsson, Wendy Bussen, Stephen Van Komen, Jian Qin, Harry van Steeg, et al. "Differential Contributions of Mammalian Rad54 Paralogs to Recombination, DNA Damage Repair, and Meiosis." Molecular and Cellular Biology 26, no. 3 (February 1, 2006): 976–89. http://dx.doi.org/10.1128/mcb.26.3.976-989.2006.

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ABSTRACT Homologous recombination is a versatile DNA damage repair pathway requiring Rad51 and Rad54. Here we show that a mammalian Rad54 paralog, Rad54B, displays physical and functional interactions with Rad51 and DNA that are similar to those of Rad54. While ablation of Rad54 in mouse embryonic stem (ES) cells leads to a mild reduction in homologous recombination efficiency, the absence of Rad54B has little effect. However, the absence of both Rad54 and Rad54B dramatically reduces homologous recombination efficiency. Furthermore, we show that Rad54B protects ES cells from ionizing radiation and the interstrand DNA cross-linking agent mitomycin C. Interestingly, at the ES cell level the paralogs do not display an additive or synergic interaction with respect to mitomycin C sensitivity, yet animals lacking both Rad54 and Rad54B are dramatically sensitized to mitomycin C compared to either single mutant. This suggests that the paralogs possibly function in a tissue-specific manner. Finally, we show that Rad54, but not Rad54B, is needed for a normal distribution of Rad51 on meiotic chromosomes. Thus, even though the paralogs have similar biochemical properties, genetic analysis in mice uncovered their nonoverlapping roles.

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Takata, Minoru, Masao S. Sasaki, Eiichiro Sonoda, Toru Fukushima, Ciaran Morrison, Joanna S. Albala, Sigrid M. A. Swagemakers, Roland Kanaar, Larry H. Thompson, and Shunichi Takeda. "The Rad51 Paralog Rad51B Promotes Homologous Recombinational Repair." Molecular and Cellular Biology 20, no. 17 (September 1, 2000): 6476–82. http://dx.doi.org/10.1128/mcb.20.17.6476-6482.2000.

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ABSTRACT The highly conserved Saccharomyces cerevisiae Rad51 protein plays a central role in both mitotic and meiotic homologous DNA recombination. Seven members of the Rad51 family have been identified in vertebrate cells, including Rad51, Dmc1, and five Rad51-related proteins referred to as Rad51 paralogs, which share 20 to 30% sequence identity with Rad51. In chicken B lymphocyte DT40 cells, we generated a mutant with RAD51B/RAD51L1, a member of the Rad51 family, knocked out. RAD51B −/− cells are viable, although spontaneous chromosomal aberrations kill about 20% of the cells in each cell cycle. Rad51B deficiency impairs homologous recombinational repair (HRR), as measured by targeted integration, sister chromatid exchange, and intragenic recombination at the immunoglobulin locus. RAD51B −/− cells are quite sensitive to the cross-linking agents cisplatin and mitomycin C and mildly sensitive to γ-rays. The formation of damage-induced Rad51 nuclear foci is much reduced in RAD51B −/−cells, suggesting that Rad51B promotes the assembly of Rad51 nucleoprotein filaments during HRR. These findings show that Rad51B is important for repairing various types of DNA lesions and maintaining chromosome integrity.

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Sinha, Asha, Ali Saleh, Raelene Endersby, Shek H. Yuan, Chirayu R. Chokshi, Kevin R. Brown, Bozena Kuzio, et al. "RAD51-Mediated DNA Homologous Recombination Is Independent of PTEN Mutational Status." Cancers 12, no. 11 (October 29, 2020): 3178. http://dx.doi.org/10.3390/cancers12113178.

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PTEN mutation occurs in a variety of aggressive cancers and is associated with poor patient outcomes. Recent studies have linked mutational loss of PTEN to reduced RAD51 expression and function, a key factor involved in the homologous recombination (HR) pathway. However, these studies remain controversial, as they fail to establish a definitive causal link to RAD51 expression that is PTEN-dependent, while other studies have not been able to recapitulate the relationship between the PTEN expression and the RAD51/HR function. Resolution of this apparent conundrum is essential due to the clinically-significant implication that PTEN-deficient tumors may be sensitive to poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) commonly used in the clinical management of BRCA-mutated and other HR-deficient (HRD) tumors. Methods: Primary Pten-deficient (and corresponding wild-type) mouse embryonic fibroblasts (MEFs) and astrocytes and PTEN-null human tumor cell lines and primary cells were assessed for RAD51 expression (via the Western blot analysis) and DNA damage repair analyses (via alkali comet and γH2AX foci assays). RAD51 foci analysis was used to measure HR-dependent DNA repair. Xrcc2-deficient MEFs served as an HR-deficient control, while the stable knockdown of RAD51 (shRAD51) served to control for the relative RAD51/HR-mediated repair and the phospho-53BP1 foci analysis served to confirm and measure non-homologous end joining (NHEJ) activity in PTEN-deficient and shRAD51-expressing (HRD) lines. Cell proliferation studies were used to measure any potential added sensitivity of PTEN-null cells to the clinically-relevant PARPi, olaparib. RAD51 levels and DNA damage response signaling were assessed in PTEN-mutant brain tumor initiating cells (BTICs) derived from primary and recurrent glioblastoma multiforme (GBM) patients, while expression of RAD51 and its paralogs were examined as a function of the PTEN status in the RNA expression datasets isolated from primary GBM tumor specimens and BTICs. Results: Pten knockout primary murine cells display unaltered RAD51 expression, endogenous and DNA strand break-induced RAD51 foci and robust DNA repair activity. Defective HR was only observed in the cells lacking Xrcc2. Likewise, human glioblastoma multiforme (GBM) cell lines with known PTEN deficiency (U87, PTEN-mutated; U251 and U373, PTEN-null) show apparent expression of RAD51 and display efficient DNA repair activity. Only GBM cells stably expressing shRNAs against RAD51 (shRAD51) display dysfunctional DNA repair activity and reduced proliferative capacity, which is exacerbated by PARPi treatment. Furthermore, GBM patient-derived BTICs displayed robust RAD51 expression and intact DNA damage response signaling in spite of PTEN-inactivating mutations. RNA expression analysis of primary GBM tissue specimens and BTICs demonstrate stable levels of RAD51 and its paralogs (RAD51B, RAD51C, RAD51D, XRCC2, XRCC3, and DMC1), regardless of the PTEN mutational status. Conclusions: Our findings demonstrate definitively that PTEN loss does not alter the RAD51 expression, its paralogs, or the HR activity. Furthermore, deficiency in PTEN alone is not sufficient to impart enhanced sensitivity to PARPi associated with HRD. This study is the first to unequivocally demonstrate that PTEN deficiency is not linked to the RAD51 expression or the HR activity amongst primary neural and non-neural Pten-null cells, PTEN-deficient tumor cell lines, and primary PTEN-mutant GBM patient-derived tissue specimens and BTICs.

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van Veelen, Lieneke R., Jeroen Essers, Mandy W. M. M. van de Rakt, Hanny Odijk, Albert Pastink, Małgorzata Z. Zdzienicka, Coen C. Paulusma, and Roland Kanaar. "Ionizing radiation-induced foci formation of mammalian Rad51 and Rad54 depends on the Rad51 paralogs, but not on Rad52." Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 574, no. 1-2 (July 2005): 34–49. http://dx.doi.org/10.1016/j.mrfmmm.2005.01.020.

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Alagpulinsa, David, Srinivas Ayyadevara, Shmuel Yaccoby, and Robert shmookler Reis. "A Peptide Nucleic Acid Targeting Nuclear Rad51 Sensitizes Myeloma Cells to Melphalan Chemotoxicity Both in Vitro and in Vivo." Blood 124, no. 21 (December 6, 2014): 3529. http://dx.doi.org/10.1182/blood.v124.21.3529.3529.

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Abstract Multiple myeloma (MM) cells are characterized by extensive genomic heterogeneity, which contributes to patient differences in prognosis and response to treatment. We previously reported that MM cells have elevated homologous recombination (HR) rates and expression of RAD51 and its paralogs, promoting genomic instability and disease progression that are reversed by RAD51 siRNA. We now examine the roles of HR and RAD51 in resistance to melphalan, one of the most widely used drugs for MM chemotherapy. The drug induces a variety of DNA lesions, with DNA interstrand crosslinks (ICL) accounting for most of the drug’s cytotoxicity. RAD51 is a central protein in the HR pathway and its overexpression may contribute to chemoresistance by enabling repair of DNA lesions induced by DNA damaging agents such as melphalan. MM cell sensitivity to melphalan correlates directly with melphalan-induced RAD51 foci, and high RAD51 expression predicts poor event-free and overall survival of MM patients. Activity of the Rad51 promoter increases >850-fold in cancer cells compared to normal cells, and tumor cells are selectively killed by a construct in which PRad51 drives expression of diphtheria toxin. In this study, we tested whether inhibiting RAD51 expression with a peptide nucleic acid (PNA) would inhibit MM cell growth and/or sensitize MM cells to melphalan. PNAs are DNA or RNA mimics in which a polymer of (2-aminoethyl) glycine replaces the nucleic acid’s sugar-phosphate backbone. PNAs are highly specific, binding DNA with higher affinity than RNA or DNA, and they are quite stable to degradation both in vitro and in vivo. We designed a PNA to target the promoter region of the RAD51 gene (PNArad51), encompassing the transcription start site. To enhance cellular uptake and nuclear delivery without transfection, we conjugated the PNA to a nuclear localization signal rich in basic residues (PKKKRKVR). As a control we employed a scrambled PNA (PNAmt) with the same nucleotide composition but not targeting any genomic sequences. We used qRT-PCR to assess the effect of PNA on RAD51 mRNA expression and that of melphalan on mRNA levels of RAD51 and its paralogs (RAD51B, RAD51B, RAD51C, RAD51D, XRCC2 and XRCC3) and BRCA1. Propidium iodide staining and flow cytometry were used to examine the cell-cycle effects of melphalan. γH2AX and RAD51 foci were quantitated using confocal immunofluorescence microscopy, and MM cell viability was assessed with the WST-1 assay. To examine the in vivo consequences of PNA ± melphalan for tumor growth, we injected H929 MM cells expressing luciferase into rabbit bone fragments implanted in SCID-rab mice, as previously described by us,. Total RNA extracted from cells recovered from the rabbit bones was analyzed by qRT-PCR to determine the in vivo effect of PNA on expression of RAD51. Melphalan treatment (10 µM) significantly induced expression of RAD51 and its paralogs, particularly RAD51 and XRCC3 (p≤0.01). Melphalan caused cell-cycle arrest, predominantly in the S-phase (55%, significantly elevated over vehicle alone, 17%; p<0.0001), the period in which HR is most active, and during which ICLs are converted into double strand breaks (DSBs) on encountering DNA replication forks. PNArad51 (10 µM) significantly reduced expression of RAD51 (~60%, p<0.001) relative to PNAmt. Pretreatment with PNArad51 inhibited melphalan-induced RAD51 focus formation, far more than PNAmt pretreatment (21% compared to 66%, p<0.0001) whereas the number of γH2AX foci increased (66%) relative to PNAmt (39%; p<0.0001). Consequently, pretreatment with PNArad51 produced synergistic synthetic lethality with melphalan, reducing the IC50 of melphalan by 4.5-fold. PNArad51 alone caused significant cytotoxicity compared to PNAmt (p<0.05). In the SCID-rab mouse model, a two-week treatment with PNArad51 alone or in combination with melphalan resulted in significant inhibition of tumor volume (p≈0.01 and p<0.05, respectively) compared to PNAmt, although the combination of PNAmt plus melphalan was ineffectual. Prolonged treatment (4 weeks) with PNArad51 ± melphalan (but not PNAmt + melphalan) reduced tumor growth compared to PNAmt treatment, although this was not statistically significant (p>0.05). These results highlight the importance of RAD51 in the response of MM cells to melphalan, and indicate for the first time the potential for RAD51-targeted PNA in tumor chemosensitization. Disclosures No relevant conflicts of interest to declare.

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Takata, Minoru, Masao S. Sasaki, Seiji Tachiiri, Toru Fukushima, Eiichiro Sonoda, David Schild, Larry H. Thompson, and Shunichi Takeda. "Chromosome Instability and Defective Recombinational Repair in Knockout Mutants of the Five Rad51 Paralogs." Molecular and Cellular Biology 21, no. 8 (April 15, 2001): 2858–66. http://dx.doi.org/10.1128/mcb.21.8.2858-2866.2001.

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ABSTRACT The Rad51 protein, a eukaryotic homologue of Escherichia coli RecA, plays a central role in both mitotic and meiotic homologous DNA recombination (HR) in Saccharomyces cerevisiae and is essential for the proliferation of vertebrate cells. Five vertebrate genes, RAD51B, -C, and -D and XRCC2 and -3, are implicated in HR on the basis of their sequence similarity to Rad51 (Rad51 paralogs). We generated mutants deficient in each of these proteins in the chicken B-lymphocyte DT40 cell line and report here the comparison of four new mutants and their complemented derivatives with our previously reported rad51b mutant. The Rad51 paralog mutations all impair HR, as measured by targeted integration and sister chromatid exchange. Remarkably, the mutant cell lines all exhibit very similar phenotypes: spontaneous chromosomal aberrations, high sensitivity to killing by cross-linking agents (mitomycin C and cisplatin), mild sensitivity to gamma rays, and significantly attenuated Rad51 focus formation during recombinational repair after exposure to gamma rays. Moreover, all mutants show partial correction of resistance to DNA damage by overexpression of human Rad51. We conclude that the Rad51 paralogs participate in repair as a functional unit that facilitates the action of Rad51 in HR.

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Somyajit, Kumar, Shivakumar Basavaraju, Ralph Scully, and Ganesh Nagaraju. "ATM- and ATR-Mediated Phosphorylation of XRCC3 Regulates DNA Double-Strand Break-Induced Checkpoint Activation and Repair." Molecular and Cellular Biology 33, no. 9 (February 25, 2013): 1830–44. http://dx.doi.org/10.1128/mcb.01521-12.

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The RAD51 paralogs XRCC3 and RAD51C have been implicated in homologous recombination (HR) and DNA damage responses. However, the molecular mechanism(s) by which these paralogs regulate HR and DNA damage signaling remains obscure. Here, we show that an SQ motif serine 225 in XRCC3 is phosphorylated by ATR kinase in an ATM signaling pathway. We find that RAD51C but not XRCC2 is essential for XRCC3 phosphorylation, and this modification follows end resection and is specific to S and G 2 phases. XRCC3 phosphorylation is required for chromatin loading of RAD51 and HR-mediated repair of double-strand breaks (DSBs). Notably, in response to DSBs, XRCC3 participates in the intra-S-phase checkpoint following its phosphorylation and in the G 2 /M checkpoint independently of its phosphorylation. Strikingly, we find that XRCC3 distinctly regulates recovery of stalled and collapsed replication forks such that phosphorylation is required for the HR-mediated recovery of collapsed replication forks but is dispensable for the restart of stalled replication forks. Together, these findings suggest that XRCC3 is a new player in the ATM/ATR-induced DNA damage responses to control checkpoint and HR-mediated repair.

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Wiese, C. "Interactions involving the Rad51 paralogs Rad51C and XRCC3 in human cells." Nucleic Acids Research 30, no. 4 (February 15, 2002): 1001–8. http://dx.doi.org/10.1093/nar/30.4.1001.

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Liu, N. "Involvement of Rad51C in two distinct protein complexes of Rad51 paralogs in human cells." Nucleic Acids Research 30, no. 4 (February 15, 2002): 1009–15. http://dx.doi.org/10.1093/nar/30.4.1009.

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Bonilla, Braulio, Sarah R. Hengel, McKenzie K. Grundy, and Kara A. Bernstein. "RAD51 Gene Family Structure and Function." Annual Review of Genetics 54, no. 1 (November 23, 2020): 25–46. http://dx.doi.org/10.1146/annurev-genet-021920-092410.

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Accurate DNA repair and replication are critical for genomic stability and cancer prevention. RAD51 and its gene family are key regulators of DNA fidelity through diverse roles in double-strand break repair, replication stress, and meiosis. RAD51 is an ATPase that forms a nucleoprotein filament on single-stranded DNA. RAD51 has the function of finding and invading homologous DNA sequences to enable accurate and timely DNA repair. Its paralogs, which arose from ancient gene duplications of RAD51, have evolved to regulate and promote RAD51 function. Underscoring its importance, misregulation of RAD51, and its paralogs, is associated with diseases such as cancer and Fanconi anemia. In this review, we focus on the mammalian RAD51 structure and function and highlight the use of model systems to enable mechanistic understanding of RAD51 cellular roles. We also discuss how misregulation of the RAD51 gene family members contributes to disease and consider new approaches to pharmacologically inhibit RAD51.

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Sullivan, Katherine, Kimberly Cramer-Morales, Daniel L. McElroy, David Ostrov, Kimberly Haas, Margaret Nieborowska-Skorska, Wayne Childers, et al. "Identification of a Small Molecule Inhibitor of RAD52 to Induce Synthetic Lethality in BRCA-Deficient Leukemias." Blood 126, no. 23 (December 3, 2015): 4434. http://dx.doi.org/10.1182/blood.v126.23.4434.4434.

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Abstract Altered DNA repair mechanisms are responsible for survival of leukemia stem cells (LSCs) and/or leukemia progenitor cells (LPCs) accumulating numerous lethal DNA double-strand breaks (DSBs). DSBs resulting from stalled/broken replication forks in proliferating cells are primarily repaired by RAD51-mediated homologous recombination repair (HR), which depends on BRCA1-PALB2-BRCA2-RAD51 paralogs (BRCA pathway), while RAD52 pathway serves as redundant back-up mechanism. Enhanced self-renewal of LSCs and high proliferation rate of LPCs commit them to HR. It has been reported that inhibition of RAD52 either by the knockout, specific shRNA, or a small peptide aptamer induced synthetic lethality in BRCA pathway-deficient tumor cell lines and primary leukemia cells. Yet pharmacological inhibition of RAD52, which binds single-stranded DNA (ssDNA) and lacks enzymatic activity, has not been demonstrated. Here, we applied high-throughput screening and structure-based selection followed by biochemical assays and computer modeling to identify three leading compounds: (1) 20264, (2) RU-0084339, and (3) D-I03. Compound 20264 appeared to interact with the hotspot in RAD52 DNA binding domain 1 to interfere with ssDNA binding. RU-0084339 is a major allosteric inhibitor of RAD52 ssDNA binding domain which disassembles undecamer ring structure of RAD52. D-I03 abrogated RAD52-mediated ssDNA annealing and ssDNA pairing. RAD52 small molecule inhibitor (RAD52smi) reduced recruitment of RAD52 to DNA damage-induced nuclear foci and suppressed RAD52-mediated DNA double-strand break (DSB) repair activity in cells with negligible effects on other DSB repair pathways. Importantly, RAD52smi selectively eliminated cancer cell lines carrying BRCA1/2 inactivating mutations. Since inactivating mutations in BRCA pathway are rare in leukemias, individual BRCA pathway-deficient leukemias were identified by Gene Expression and Mutation Analysis (GEMA). Gene Expression approach applied microarrays, qRT-PCR, and/or flow cytometry to identify individual leukemias displaying downregulation of at least one gene in BRCA pathway. On the other hand, Gene Mutation strategy detected individual leukemias expressing an oncogene causing downregulation of BRCA pathway gene(s) (e.g., BCR-ABL1, MLL-AF9, AML1-ETO - mediated downregulation of BRCA1 and/or BRCA2) and harboring inactivating mutations in BRCA pathway (e.g., BRCA2 = FANCD1, and other FA genes). BRCA-deficient cells from individual patients indentified by GEMA were selectively sensitive to RAD52smi alone or in combination with already approved cytotoxic drugs. RAD52 is a promising new target because it is "druggable" by small molecule inhibitors. Moreover, inhibition of RAD52 by genetic knockout and small peptide aptamer did not exert any major negative effects in normal cells and tissues. Altogether, this work provided foundation for precision medicine guided synthetic lethality in BRCA-deficient leukemias exerted by small molecule inhibitors targeting novel mechanism - RAD52 dependent DSB repair. Disclosures No relevant conflicts of interest to declare.

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Taylor, Martin R. G., Mário Špírek, Kathy R. Chaurasiya, Jordan D. Ward, Raffaella Carzaniga, Xiong Yu, Edward H. Egelman, et al. "Rad51 Paralogs Remodel Pre-synaptic Rad51 Filaments to Stimulate Homologous Recombination." Cell 162, no. 2 (July 2015): 271–86. http://dx.doi.org/10.1016/j.cell.2015.06.015.

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Taylor, Martin R. G., Mário Špírek, Chu Jian Ma, Raffaella Carzaniga, Tohru Takaki, Lucy M. Collinson, Eric C. Greene, Lumir Krejci, and Simon J. Boulton. "A Polar and Nucleotide-Dependent Mechanism of Action for RAD51 Paralogs in RAD51 Filament Remodeling." Molecular Cell 64, no. 5 (December 2016): 926–39. http://dx.doi.org/10.1016/j.molcel.2016.10.020.

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Cejka, Petr. "Single-molecule studies illuminate the function of RAD51 paralogs." Molecular Cell 81, no. 5 (March 2021): 898–900. http://dx.doi.org/10.1016/j.molcel.2021.01.037.

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Schild, David, Yi-ching Lio, David W. Collins, Tswakai Tsomondo, and David J. Chen. "Evidence for Simultaneous Protein Interactions between Human Rad51 Paralogs." Journal of Biological Chemistry 275, no. 22 (April 3, 2000): 16443–49. http://dx.doi.org/10.1074/jbc.m001473200.

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Bhattacharya, Debanjali, Satyaranjan Sahoo, Tarun Nagraj, Suruchi Dixit, Harsh Kumar Dwivedi, and Ganesh Nagaraju. "RAD51 paralogs: Expanding roles in replication stress responses and repair." Current Opinion in Pharmacology 67 (December 2022): 102313. http://dx.doi.org/10.1016/j.coph.2022.102313.

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Adelman, Carrie A., Rafal L. Lolo, Nicolai J. Birkbak, Olga Murina, Kenichiro Matsuzaki, Zuzana Horejsi, Kalindi Parmar, et al. "HELQ promotes RAD51 paralogue-dependent repair to avert germ cell loss and tumorigenesis." Nature 502, no. 7471 (September 4, 2013): 381–84. http://dx.doi.org/10.1038/nature12565.

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Anand, Roopesh, Erika Buechelmaier, Ondrej Belan, Matthew Newton, Aleksandra Vancevska, Artur Kaczmarczyk, Tohru Takaki, David S. Rueda, Simon N. Powell, and Simon J. Boulton. "HELQ is a dual-function DSB repair enzyme modulated by RPA and RAD51." Nature 601, no. 7892 (December 22, 2021): 268–73. http://dx.doi.org/10.1038/s41586-021-04261-0.

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AbstractDNA double-stranded breaks (DSBs) are deleterious lesions, and their incorrect repair can drive cancer development1. HELQ is a superfamily 2 helicase with 3′ to 5′ polarity, and its disruption in mice confers germ cells loss, infertility and increased predisposition to ovarian and pituitary tumours2–4. At the cellular level, defects in HELQ result in hypersensitivity to cisplatin and mitomycin C, and persistence of RAD51 foci after DNA damage3,5. Notably, HELQ binds to RPA and the RAD51-paralogue BCDX2 complex, but the relevance of these interactions and how HELQ functions in DSB repair remains unclear3,5,6. Here we show that HELQ helicase activity and a previously unappreciated DNA strand annealing function are differentially regulated by RPA and RAD51. Using biochemistry analyses and single-molecule imaging, we establish that RAD51 forms a complex with and strongly stimulates HELQ as it translocates during DNA unwinding. By contrast, RPA inhibits DNA unwinding by HELQ but strongly stimulates DNA strand annealing. Mechanistically, we show that HELQ possesses an intrinsic ability to capture RPA-bound DNA strands and then displace RPA to facilitate annealing of complementary sequences. Finally, we show that HELQ deficiency in cells compromises single-strand annealing and microhomology-mediated end-joining pathways and leads to bias towards long-tract gene conversion tracts during homologous recombination. Thus, our results implicate HELQ in multiple arms of DSB repair through co-factor-dependent modulation of intrinsic translocase and DNA strand annealing activities.

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Rodrigue, Amélie, Yan Coulombe, Karine Jacquet, Jean-Phillipe Gagné, Céline Roques, Stéphane Gobeil, Guy Poirier, and Jean-Yves Masson. "The RAD51 paralogs ensure cellular protection against mitotic defects and aneuploidy." Journal of Cell Science 126, no. 1 (October 29, 2012): 348–59. http://dx.doi.org/10.1242/jcs.114595.

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Genois, Marie-Michelle, Marie Plourde, Chantal Éthier, Gaétan Roy, Guy G. Poirier, Marc Ouellette, and Jean-Yves Masson. "Roles of Rad51 paralogs for promoting homologous recombination in Leishmania infantum." Nucleic Acids Research 43, no. 5 (February 24, 2015): 2701–15. http://dx.doi.org/10.1093/nar/gkv118.

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Suwaki, Natsuko, Kerstin Klare, and Madalena Tarsounas. "RAD51 paralogs: Roles in DNA damage signalling, recombinational repair and tumorigenesis." Seminars in Cell & Developmental Biology 22, no. 8 (October 2011): 898–905. http://dx.doi.org/10.1016/j.semcdb.2011.07.019.

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Ordinario, Ellen C., Munehisa Yabuki, Priya Handa, W. Jason Cummings, and Nancy Maizels. "RAD51 paralogs promote homology-directed repair at diversifying immunoglobulin V regions." BMC Molecular Biology 10, no. 1 (2009): 98. http://dx.doi.org/10.1186/1471-2199-10-98.

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Masson, J. Y. "Identification and purification of two distinct complexes containing the five RAD51 paralogs." Genes & Development 15, no. 24 (December 15, 2001): 3296–307. http://dx.doi.org/10.1101/gad.947001.

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Jensen, Ryan B., Ali Ozes, Taeho Kim, Allison Estep, and Stephen C. Kowalczykowski. "BRCA2 is epistatic to the RAD51 paralogs in response to DNA damage." DNA Repair 12, no. 4 (April 2013): 306–11. http://dx.doi.org/10.1016/j.dnarep.2012.12.007.

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Bleuyard, Jean-Yves, Maria E. Gallego, Florence Savigny, and Charles I. White. "Differing requirements for the Arabidopsis Rad51 paralogs in meiosis and DNA repair." Plant Journal 41, no. 4 (December 22, 2004): 533–45. http://dx.doi.org/10.1111/j.1365-313x.2004.02318.x.

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Somyajit, Kumar, Sneha Saxena, Sharath Babu, Anup Mishra, and Ganesh Nagaraju. "Mammalian RAD51 paralogs protect nascent DNA at stalled forks and mediate replication restart." Nucleic Acids Research 48, no. 9 (April 17, 2020): 5196–97. http://dx.doi.org/10.1093/nar/gkaa279.

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Xu, Zhan, Jianxiang Zhang, Meng Xu, Wen Ji, Meimei Yu, Yajun Tao, Zhiyun Gong, Minghong Gu, and Hengxiu Yu. "Rice RAD51 paralogs play essential roles in somatic homologous recombination for DNA repair." Plant Journal 95, no. 2 (June 6, 2018): 282–95. http://dx.doi.org/10.1111/tpj.13949.

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Harris, Janelle Louise, Andrea Rabellino, and Kum Kum Khanna. "RAD51 paralogs promote genomic integrity and chemoresistance in cancer by facilitating homologous recombination." Annals of Translational Medicine 6, S2 (December 2018): S122. http://dx.doi.org/10.21037/atm.2018.12.30.

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Grešner, Peter, Ewa Jabłońska, and Jolanta Gromadzińska. "Rad51 paralogs and the risk of unselected breast cancer: A case-control study." PLOS ONE 15, no. 1 (January 6, 2020): e0226976. http://dx.doi.org/10.1371/journal.pone.0226976.

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Özer, Hanna, Daniel Wasser, Lara Sandner, and Jörg Soppa. "Intermolecular Gene Conversion for the Equalization of Genome Copies in the Polyploid Haloarchaeon Haloferax volcanii: Identification of Important Proteins." Genes 15, no. 7 (July 1, 2024): 861. http://dx.doi.org/10.3390/genes15070861.

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The model haloarchaeon Haloferax volcanii is polyploid with about 20 copies of its major chromosome. Recently it has been described that highly efficient intermolecular gene conversion operates in H. volcanii to equalize the chromosomal copies. In the current study, 24 genes were selected that encode proteins with orthologs involved in gene conversion or homologous recombination in archaea, bacteria, or eukaryotes. Single gene deletion strains of 22 genes and a control gene were constructed in two parent strains for a gene conversion assay; only radA and radB were shown to be essential. Protoplast fusions were used to generate strains that were heterozygous for the gene HVO_2528, encoding an enzyme for carotinoid biosynthesis. It was revealed that a lack of six of the proteins did not influence the efficiency of gene conversion, while sixteen mutants had severe gene conversion defects. Notably, lack of paralogous proteins of gene families had very different effects, e.g., mutant Δrad25b had no phenotype, while mutants Δrad25a, Δrad25c, and Δrad25d were highly compromised. Generation of a quadruple rad25 and a triple sph deletion strain also indicated that the paralogs have different functions, in contrast to sph2 and sph4, which cannot be deleted simultaneously. There was no correlation between the severity of the phenotypes and the respective transcript levels under non-stressed conditions, indicating that gene expression has to be induced at the onset of gene conversion. Phylogenetic trees of the protein families Rad3/25, MutL/S, and Sph/SMC/Rad50 were generated to unravel the history of the paralogous proteins of H. volcanii. Taken together, unselected intermolecular gene conversion in H. volcanii involves at least 16 different proteins, the molecular roles of which can be studied in detail in future projects.

Journal articles on the topic 'Paralogues de Rad51'

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