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Journal articles on the topic 'Fork reversal'

Author: Grafiati

Published: 9 March 2023

Last updated: 10 March 2023

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1

Bhat, Kamakoti P., and David Cortez. "RPA and RAD51: fork reversal, fork protection, and genome stability." Nature Structural & Molecular Biology 25, no. 6 (May 28, 2018): 446–53. http://dx.doi.org/10.1038/s41594-018-0075-z.

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2

Fierro-Fernandez, M., P. Hernandez, D. B. Krimer, A. Stasiak, and J. B. Schvartzman. "Topological locking restrains replication fork reversal." Proceedings of the National Academy of Sciences 104, no. 5 (January 22, 2007): 1500–1505. http://dx.doi.org/10.1073/pnas.0609204104.

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3

Quinet, Annabel, Delphine Lemaçon, and Alessandro Vindigni. "Replication Fork Reversal: Players and Guardians." Molecular Cell 68, no. 5 (December 2017): 830–33. http://dx.doi.org/10.1016/j.molcel.2017.11.022.

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4

Batenburg, Nicole L., Sofiane Y. Mersaoui, John R. Walker, Yan Coulombe, Ian Hammond-Martel, Hugo Wurtele, Jean-Yves Masson, and Xu-Dong Zhu. "Cockayne syndrome group B protein regulates fork restart, fork progression and MRE11-dependent fork degradation in BRCA1/2-deficient cells." Nucleic Acids Research 49, no. 22 (December 6, 2021): 12836–54. http://dx.doi.org/10.1093/nar/gkab1173.

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Abstract Cockayne syndrome group B (CSB) protein has been implicated in the repair of a variety of DNA lesions that induce replication stress. However, little is known about its role at stalled replication forks. Here, we report that CSB is recruited to stalled forks in a manner dependent upon its T1031 phosphorylation by CDK. While dispensable for MRE11 association with stalled forks in wild-type cells, CSB is required for further accumulation of MRE11 at stalled forks in BRCA1/2-deficient cells. CSB promotes MRE11-mediated fork degradation in BRCA1/2-deficient cells. CSB possesses an intrinsic ATP-dependent fork reversal activity in vitro, which is activated upon removal of its N-terminal region that is known to autoinhibit CSB’s ATPase domain. CSB functions similarly to fork reversal factors SMARCAL1, ZRANB3 and HLTF to regulate slowdown in fork progression upon exposure to replication stress, indicative of a role of CSB in fork reversal in vivo. Furthermore, CSB not only acts epistatically with MRE11 to facilitate fork restart but also promotes RAD52-mediated break-induced replication repair of double-strand breaks arising from cleavage of stalled forks by MUS81 in BRCA1/2-deficient cells. Loss of CSB exacerbates chemosensitivity in BRCA1/2-deficient cells, underscoring an important role of CSB in the treatment of cancer lacking functional BRCA1/2.

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5

Liu, W., A. Krishnamoorthy, R. Zhao, and D. Cortez. "Two replication fork remodeling pathways generate nuclease substrates for distinct fork protection factors." Science Advances 6, no. 46 (November 2020): eabc3598. http://dx.doi.org/10.1126/sciadv.abc3598.

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Fork reversal is a common response to replication stress, but it generates a DNA end that is susceptible to degradation. Many fork protection factors block degradation, but how they work remains unclear. Here, we find that 53BP1 protects forks from DNA2-mediated degradation in a cell type–specific manner. Fork protection by 53BP1 reduces S-phase DNA damage and hypersensitivity to replication stress. Unlike BRCA2, FANCD2, and ABRO1 that protect reversed forks generated by SMARCAL1, ZRANB3, and HLTF, 53BP1 protects forks remodeled by FBH1. This property is shared by the fork protection factors FANCA, FANCC, FANCG, BOD1L, and VHL. RAD51 is required to generate the resection substrate in all cases. Unexpectedly, BRCA2 is also required for fork degradation in the FBH1 pathway or when RAD51 activity is partially compromised. We conclude that there are multiple fork protection mechanisms that operate downstream of at least two RAD51-dependent fork remodeling pathways.

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6

Thakar, Tanay, and George-Lucian Moldovan. "The emerging determinants of replication fork stability." Nucleic Acids Research 49, no. 13 (May 12, 2021): 7224–38. http://dx.doi.org/10.1093/nar/gkab344.

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Abstract A universal response to replication stress is replication fork reversal, where the nascent complementary DNA strands are annealed to form a protective four-way junction allowing forks to avert DNA damage while replication stress is resolved. However, reversed forks are in turn susceptible to nucleolytic digestion of the regressed nascent DNA arms and rely on dedicated mechanisms to protect their integrity. The most well studied fork protection mechanism involves the BRCA pathway and its ability to catalyze RAD51 nucleofilament formation on the reversed arms of stalled replication forks. Importantly, the inability to prevent the degradation of reversed forks has emerged as a hallmark of BRCA deficiency and underlies genome instability and chemosensitivity in BRCA-deficient cells. In the past decade, multiple factors underlying fork stability have been discovered. These factors either cooperate with the BRCA pathway, operate independently from it to augment fork stability in its absence, or act as enablers of fork degradation. In this review, we examine these novel determinants of fork stability, explore the emergent conceptual underpinnings underlying fork protection, as well as the impact of fork protection on cellular viability and cancer therapy.

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7

Le Masson, Marie, Zeynep Baharoglu, and Bénédicte Michel. "ruvAandruvBmutants specifically impaired for replication fork reversal." Molecular Microbiology 70, no. 2 (October 2008): 537–48. http://dx.doi.org/10.1111/j.1365-2958.2008.06431.x.

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8

De Septenville, Anne L., Stéphane Duigou, Hasna Boubakri, and Bénédicte Michel. "Replication Fork Reversal after Replication–Transcription Collision." PLoS Genetics 8, no. 4 (April 5, 2012): e1002622. http://dx.doi.org/10.1371/journal.pgen.1002622.

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9

Krishnamoorthy, Archana, Jessica Jackson, Taha Mohamed, Madison Adolph, Alessandro Vindigni, and David Cortez. "RADX prevents genome instability by confining replication fork reversal to stalled forks." Molecular Cell 81, no. 14 (July 2021): 3007–17. http://dx.doi.org/10.1016/j.molcel.2021.05.014.

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10

Torres, Rubén, Carolina Gándara, Begoña Carrasco, Ignacio Baquedano, Silvia Ayora, and Juan C. Alonso. "DisA Limits RecG Activities at Stalled or Reversed Replication Forks." Cells 10, no. 6 (May 31, 2021): 1357. http://dx.doi.org/10.3390/cells10061357.

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The DNA damage checkpoint protein DisA and the branch migration translocase RecG are implicated in the preservation of genome integrity in reviving haploid Bacillus subtilis spores. DisA synthesizes the essential cyclic 3′, 5′-diadenosine monophosphate (c-di-AMP) second messenger and such synthesis is suppressed upon replication perturbation. In vitro, c-di-AMP synthesis is suppressed when DisA binds DNA structures that mimic stalled or reversed forks (gapped forks or Holliday junctions [HJ]). RecG, which does not form a stable complex with DisA, unwinds branched intermediates, and in the presence of a limiting ATP concentration and HJ DNA, it blocks DisA-mediated c-di-AMP synthesis. DisA pre-bound to a stalled or reversed fork limits RecG-mediated ATP hydrolysis and DNA unwinding, but not if RecG is pre-bound to stalled or reversed forks. We propose that RecG-mediated fork remodeling is a genuine in vivo activity, and that DisA, as a molecular switch, limits RecG-mediated fork reversal and fork restoration. DisA and RecG might provide more time to process perturbed forks, avoiding genome breakage.

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11

Couch, Frank B., and David Cortez. "Fork reversal, too much of a good thing." Cell Cycle 13, no. 7 (February 18, 2014): 1049–50. http://dx.doi.org/10.4161/cc.28212.

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12

Zellweger, Ralph, Damian Dalcher, Karun Mutreja, Matteo Berti, Jonas A. Schmid, Raquel Herrador, Alessandro Vindigni, and Massimo Lopes. "Rad51-mediated replication fork reversal is a global response to genotoxic treatments in human cells." Journal of Cell Biology 208, no. 5 (March 2, 2015): 563–79. http://dx.doi.org/10.1083/jcb.201406099.

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Replication fork reversal protects forks from breakage after poisoning of Topoisomerase 1. We here investigated fork progression and chromosomal breakage in human cells in response to a panel of sublethal genotoxic treatments, using other topoisomerase poisons, DNA synthesis inhibitors, interstrand cross-linking inducers, and base-damaging agents. We used electron microscopy to visualize fork architecture under these conditions and analyzed the association of specific molecular features with checkpoint activation. Our data identify replication fork uncoupling and reversal as global responses to genotoxic treatments. Both events are frequent even after mild treatments that do not affect fork integrity, nor activate checkpoints. Fork reversal was found to be dependent on the central homologous recombination factor RAD51, which is consistently present at replication forks independently of their breakage, and to be antagonized by poly (ADP-ribose) polymerase/RECQ1-regulated restart. Our work establishes remodeling of uncoupled forks as a pivotal RAD51-regulated response to genotoxic stress in human cells and as a promising target to potentiate cancer chemotherapy.

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13

Thangavel, Saravanabhavan, Matteo Berti, Maryna Levikova, Cosimo Pinto, Shivasankari Gomathinayagam, Marko Vujanovic, Ralph Zellweger, et al. "DNA2 drives processing and restart of reversed replication forks in human cells." Journal of Cell Biology 208, no. 5 (March 2, 2015): 545–62. http://dx.doi.org/10.1083/jcb.201406100.

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Accurate processing of stalled or damaged DNA replication forks is paramount to genomic integrity and recent work points to replication fork reversal and restart as a central mechanism to ensuring high-fidelity DNA replication. Here, we identify a novel DNA2- and WRN-dependent mechanism of reversed replication fork processing and restart after prolonged genotoxic stress. The human DNA2 nuclease and WRN ATPase activities functionally interact to degrade reversed replication forks with a 5′-to-3′ polarity and promote replication restart, thus preventing aberrant processing of unresolved replication intermediates. Unexpectedly, EXO1, MRE11, and CtIP are not involved in the same mechanism of reversed fork processing, whereas human RECQ1 limits DNA2 activity by preventing extensive nascent strand degradation. RAD51 depletion antagonizes this mechanism, presumably by preventing reversed fork formation. These studies define a new mechanism for maintaining genome integrity tightly controlled by specific nucleolytic activities and central homologous recombination factors.

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14

Sogo, J. M. "Fork Reversal and ssDNA Accumulation at Stalled Replication Forks Owing to Checkpoint Defects." Science 297, no. 5581 (July 26, 2002): 599–602. http://dx.doi.org/10.1126/science.1074023.

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15

Cotta-Ramusino, Cecilia, Daniele Fachinetti, Chiara Lucca, Ylli Doksani, Massimo Lopes, José Sogo, and Marco Foiani. "Exo1 Processes Stalled Replication Forks and Counteracts Fork Reversal in Checkpoint-Defective Cells." Molecular Cell 17, no. 1 (January 2005): 153–59. http://dx.doi.org/10.1016/j.molcel.2004.11.032.

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16

Grompone, Gianfranco, Dusko Ehrlich, and Bénédicte Michel. "Cells defective for replication restart undergo replication fork reversal." EMBO reports 5, no. 6 (May 28, 2004): 607–12. http://dx.doi.org/10.1038/sj.embor.7400167.

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17

Atkinson, J., and P. McGlynn. "Replication fork reversal and the maintenance of genome stability." Nucleic Acids Research 37, no. 11 (April 30, 2009): 3475–92. http://dx.doi.org/10.1093/nar/gkp244.

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18

Bhattacharjee, Somendra M. "Interfacial instability and DNA fork reversal by repair proteins." Journal of Physics: Condensed Matter 22, no. 15 (March 9, 2010): 155102. http://dx.doi.org/10.1088/0953-8984/22/15/155102.

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19

Singleton, Martin R., Sarah Scaife, and Dale B. Wigley. "Structural Analysis of DNA Replication Fork Reversal by RecG." Cell 107, no. 1 (October 2001): 79–89. http://dx.doi.org/10.1016/s0092-8674(01)00501-3.

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20

Warren, Garrett, Richard Stein, Hassane Mchaourab, and Brandt Eichman. "Movement of the RecG Motor Domain upon DNA Binding Is Required for Efficient Fork Reversal." International Journal of Molecular Sciences 19, no. 10 (October 6, 2018): 3049. http://dx.doi.org/10.3390/ijms19103049.

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RecG catalyzes reversal of stalled replication forks in response to replication stress in bacteria. The protein contains a fork recognition (“wedge”) domain that binds branched DNA and a superfamily II (SF2) ATPase motor that drives translocation on double-stranded (ds)DNA. The mechanism by which the wedge and motor domains collaborate to catalyze fork reversal in RecG and analogous eukaryotic fork remodelers is unknown. Here, we used electron paramagnetic resonance (EPR) spectroscopy to probe conformational changes between the wedge and ATPase domains in response to fork DNA binding by Thermotoga maritima RecG. Upon binding DNA, the ATPase-C lobe moves away from both the wedge and ATPase-N domains. This conformational change is consistent with a model of RecG fully engaged with a DNA fork substrate constructed from a crystal structure of RecG bound to a DNA junction together with recent cryo-electron microscopy (EM) structures of chromatin remodelers in complex with dsDNA. We show by mutational analysis that a conserved loop within the translocation in RecG (TRG) motif that was unstructured in the RecG crystal structure is essential for fork reversal and DNA-dependent conformational changes. Together, this work helps provide a more coherent model of fork binding and remodeling by RecG and related eukaryotic enzymes.

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21

Jain, Chetan K., Swagata Mukhopadhyay, and Agneyo Ganguly. "RecQ Family Helicases in Replication Fork Remodeling and Repair: Opening New Avenues towards the Identification of Potential Targets for Cancer Chemotherapy." Anti-Cancer Agents in Medicinal Chemistry 20, no. 11 (July 8, 2020): 1311–26. http://dx.doi.org/10.2174/1871520620666200518082433.

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Replication fork reversal and restart has gained immense interest as a central response mechanism to replication stress following DNA damage. Although the exact mechanism of fork reversal has not been elucidated precisely, the involvement of diverse pathways and different factors has been demonstrated, which are central to this phenomenon. RecQ helicases known for their vital role in DNA repair and maintaining genome stability has recently been implicated in the restart of regressed replication forks. Through interaction with vital proteins like Poly (ADP) ribose polymerase 1 (PARP1), these helicases participate in the replication fork reversal and restart phenomenon. Most therapeutic agents used for cancer chemotherapy act by causing DNA damage in replicating cells and subsequent cell death. These DNA damages can be repaired by mechanisms involving fork reversal as the key phenomenon eventually reducing the efficacy of the therapeutic agent. Hence the factors contributing to this repair process can be good selective targets for developing more efficient chemotherapeutic agents. In this review, we have discussed in detail the role of various proteins in replication fork reversal and restart with special emphasis on RecQ helicases. Involvement of other proteins like PARP1, recombinase rad51, SWI/SNF complex has also been discussed. Since RecQ helicases play a central role in the DNA damage response following chemotherapeutic treatment, we propose that targeting these helicases can emerge as an alternative to available intervention strategies. We have also summarized the current research status of available RecQ inhibitors and siRNA based therapeutic approaches that targets RecQ helicases. In summary, our review gives an overview of the DNA damage responses involving replication fork reversal and provides new directions for the development of more efficient and sustainable chemotherapeutic approaches.

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22

Olavarrieta, L. "Supercoiling, knotting and replication fork reversal in partially replicated plasmids." Nucleic Acids Research 30, no. 3 (February 1, 2002): 656–66. http://dx.doi.org/10.1093/nar/30.3.656.

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23

Graham, Ambassador Thomas, and Douglas B. Shaw. "Nearing a fork in the road: Proliferation or nuclear reversal?" Nonproliferation Review 6, no. 1 (December 1998): 70–76. http://dx.doi.org/10.1080/10736709808436736.

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24

Ray Chaudhuri, Arnab, Yoshitami Hashimoto, Raquel Herrador, Kai J. Neelsen, Daniele Fachinetti, Rodrigo Bermejo, Andrea Cocito, Vincenzo Costanzo, and Massimo Lopes. "Topoisomerase I poisoning results in PARP-mediated replication fork reversal." Nature Structural & Molecular Biology 19, no. 4 (March 4, 2012): 417–23. http://dx.doi.org/10.1038/nsmb.2258.

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25

Khanduja, Jasbeer Singh, and K. Muniyappa. "Functional Analysis of DNA Replication Fork Reversal Catalyzed byMycobacterium tuberculosisRuvAB Proteins." Journal of Biological Chemistry 287, no. 2 (November 17, 2011): 1345–60. http://dx.doi.org/10.1074/jbc.m111.304741.

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26

Neelsen, Kai J., and Massimo Lopes. "Replication fork reversal in eukaryotes: from dead end to dynamic response." Nature Reviews Molecular Cell Biology 16, no. 4 (February 25, 2015): 207–20. http://dx.doi.org/10.1038/nrm3935.

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27

Amunugama, Ravindra, Smaranda Willcox, R. Alex Wu, Ummi B. Abdullah, Afaf H. El-Sagheer, Tom Brown, Peter J. McHugh, Jack D. Griffith, and Johannes C. Walter. "Replication Fork Reversal during DNA Interstrand Crosslink Repair Requires CMG Unloading." Cell Reports 23, no. 12 (June 2018): 3419–28. http://dx.doi.org/10.1016/j.celrep.2018.05.061.

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28

Chen, Bo-Ruei, Annabel Quinet, Andrea K. Byrum, Jessica Jackson, Matteo Berti, Saravanabhavan Thangavel, Andrea L. Bredemeyer, et al. "XLF and H2AX function in series to promote replication fork stability." Journal of Cell Biology 218, no. 7 (May 23, 2019): 2113–23. http://dx.doi.org/10.1083/jcb.201808134.

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XRCC4-like factor (XLF) is a non-homologous end joining (NHEJ) DNA double strand break repair protein. However, XLF deficiency leads to phenotypes in mice and humans that are not necessarily consistent with an isolated defect in NHEJ. Here we show that XLF functions during DNA replication. XLF undergoes cell division cycle 7–dependent phosphorylation; associates with the replication factor C complex, a critical component of the replisome; and is found at replication forks. XLF deficiency leads to defects in replication fork progression and an increase in fork reversal. The additional loss of H2AX, which protects DNA ends from resection, leads to a requirement for ATR to prevent an MRE11-dependent loss of newly synthesized DNA and activation of DNA damage response. Moreover, H2ax−/−:Xlf−/− cells exhibit a marked dependence on the ATR kinase for survival. We propose that XLF and H2AX function in series to prevent replication stress induced by the MRE11-dependent resection of regressed arms at reversed replication forks.

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29

Mutreja, Karun, Jana Krietsch, Jeannine Hess, Sebastian Ursich, Matteo Berti, Fabienne K. Roessler, Ralph Zellweger, Malay Patra, Gilles Gasser, and Massimo Lopes. "ATR-Mediated Global Fork Slowing and Reversal Assist Fork Traverse and Prevent Chromosomal Breakage at DNA Interstrand Cross-Links." Cell Reports 24, no. 10 (September 2018): 2629–42. http://dx.doi.org/10.1016/j.celrep.2018.08.019.

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30

Quinet, Annabel, Stephanie Tirman, Jessica Jackson, Saša Šviković, Delphine Lemaçon, Denisse Carvajal-Maldonado, Daniel González-Acosta, et al. "PRIMPOL-Mediated Adaptive Response Suppresses Replication Fork Reversal in BRCA-Deficient Cells." Molecular Cell 77, no. 3 (February 2020): 461–74. http://dx.doi.org/10.1016/j.molcel.2019.10.008.

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31

Honda, Masayoshi, Emeleeta A. Paintsil, and Maria Spies. "RAD52 DNA Repair Protein is a Gatekeeper that Protects DNA Replication Forks from Regression by Fork Reversal Motors." Biophysical Journal 118, no. 3 (February 2020): 160a. http://dx.doi.org/10.1016/j.bpj.2019.11.988.

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32

Mayle, Ryan, Lance Langston, Kelly R. Molloy, Dan Zhang, Brian T. Chait, and Michael E. O’Donnell. "Mcm10 has potent strand-annealing activity and limits translocase-mediated fork regression." Proceedings of the National Academy of Sciences 116, no. 3 (December 31, 2018): 798–803. http://dx.doi.org/10.1073/pnas.1819107116.

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The 11-subunit eukaryotic replicative helicase CMG (Cdc45, Mcm2-7, GINS) tightly binds Mcm10, an essential replication protein in all eukaryotes. Here we show that Mcm10 has a potent strand-annealing activity both alone and in complex with CMG. CMG-Mcm10 unwinds and then reanneals single strands soon after they have been unwound in vitro. Given the DNA damage and replisome instability associated with loss of Mcm10 function, we examined the effect of Mcm10 on fork regression. Fork regression requires the unwinding and pairing of newly synthesized strands, performed by a specialized class of ATP-dependent DNA translocases. We show here that Mcm10 inhibits fork regression by the well-known fork reversal enzyme SMARCAL1. We propose that Mcm10 inhibits the unwinding of nascent strands to prevent fork regression at normal unperturbed replication forks, either by binding the fork junction to form a block to SMARCAL1 or by reannealing unwound nascent strands to their parental template. Analysis of the CMG-Mcm10 complex by cross-linking mass spectrometry reveals Mcm10 interacts with six CMG subunits, with the DNA-binding region of Mcm10 on the N-face of CMG. This position on CMG places Mcm10 at the fork junction, consistent with a role in regulating fork regression.

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33

Guarino, Estrella, Israel Salguero, Alfonso Jiménez-Sánchez, and Elena C. Guzmán. "Double-Strand Break Generation under Deoxyribonucleotide Starvation in Escherichia coli." Journal of Bacteriology 189, no. 15 (May 25, 2007): 5782–86. http://dx.doi.org/10.1128/jb.00411-07.

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ABSTRACT Stalled replication forks produced by three different ways of depleting deoxynucleoside triphosphate showed different capacities to undergo “replication fork reversal.” This reaction occurred at the stalled forks generated by hydroxyurea treatment, was impaired under thermal inactivation of ribonucleoside reductase, and did not take place under thymine starvation.

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34

Follonier, Cindy, Judith Oehler, Raquel Herrador, and Massimo Lopes. "Friedreich's ataxia–associated GAA repeats induce replication-fork reversal and unusual molecular junctions." Nature Structural & Molecular Biology 20, no. 4 (March 3, 2013): 486–94. http://dx.doi.org/10.1038/nsmb.2520.

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35

Fierro-Fernández, Marta, Pablo Hernández, Dora B. Krimer, and Jorge B. Schvartzman. "Replication Fork Reversal Occurs Spontaneously after Digestion but Is Constrained in Supercoiled Domains." Journal of Biological Chemistry 282, no. 25 (April 23, 2007): 18190–96. http://dx.doi.org/10.1074/jbc.m701559200.

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36

Kile, Andrew C., Diana A. Chavez, Julien Bacal, Sherif Eldirany, Dmitry M. Korzhnev, Irina Bezsonova, Brandt F. Eichman, and Karlene A. Cimprich. "HLTF’s Ancient HIRAN Domain Binds 3′ DNA Ends to Drive Replication Fork Reversal." Molecular Cell 58, no. 6 (June 2015): 1090–100. http://dx.doi.org/10.1016/j.molcel.2015.05.013.

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37

Cybulla, Emily, Jessica Jackson, Stephanie Tirman, Annabel Quinet, Delphine Lemacon, and Alessandro Vindigni. "Abstract 803: Identifying a RAD18/UBC13-dependent mechanism of replication fork recovery to modulate chemoresponse in BRCA1-deficient cancers." Cancer Research 82, no. 12_Supplement (June 15, 2022): 803. http://dx.doi.org/10.1158/1538-7445.am2022-803.

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Abstract Mutations in the breast cancer susceptibility genes BRCA1 and BRCA2 are associated with an increased lifetime risk of breast and ovarian cancers. While the BRCA proteins play a well-established role in double-stranded DNA break repair, recent studies have revealed an emerging role of BRCA1/2 in replication stress response. While replication forks are extensively degraded by nucleases in BRCA-deficient cancer cells, activation of specialized fork recovery mechanisms enables resumption of DNA synthesis and promotes cell survival. My project aims to determine this fork recovery mechanism in BRCA1-deficient cells and to identify potential recovery factors that can be targeted to improve chemotherapeutic response in BRCA1-mutated breast and ovarian cancers. To monitor perturbations in replication fork dynamics on a genome-wide scale, we utilize a DNA fiber assay technique measuring rates of fork recovery and replication fork degradation. In parallel, electron microscopy analysis allows direct visualization of replication fork intermediates. Cell survival assays are employed to test how loss of fork recovery factors impacts cell proliferation and chemotherapeutic response in BRCA1-deficient cells. Our results reveal that RAD18 and UBC13, which catalyze ubiquitination of Proliferating Cellular Nuclear Antigen (PCNA), promote fork recovery in BRCA1-deficient, but not BRCA2-deficient, cancer cells. Previous work has also shown that PCNA polyubiquitination by UBC13 is important for reversed fork formation in BRCA-proficient cells. However, our findings show that extensive degradation of reversed fork substrates still occurs in BRCA1-deficient cells lacking RAD18 or UBC13, indicating that PCNA polyubiquitination is not essential for fork reversal in this genetic background. In addition, loss of RAD18 in BRCA1-deficient cells significantly slows cell proliferation, and UBC13 inhibition further sensitizes cells lacking BRCA1 to the replication stress inducer Hydroxyurea (HU). Based on our findings, we hypothesize that RAD18, UBC13, and PCNA ubiquitination may represent novel targets to improve chemoresponse in BRCA1-deficient cancers that rely on fork recovery mechanisms for survival. Citation Format: Emily Cybulla, Jessica Jackson, Stephanie Tirman, Annabel Quinet, Delphine Lemacon, Alessandro Vindigni. Identifying a RAD18/UBC13-dependent mechanism of replication fork recovery to modulate chemoresponse in BRCA1-deficient cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 803.

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38

Flores, Maria Jose, Vladimir Bidnenko, and Bénédicte Michel. "The DNA repair helicase UvrD is essential for replication fork reversal in replication mutants." EMBO reports 5, no. 10 (October 2004): 983–88. http://dx.doi.org/10.1038/sj.embor.7400262.

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39

Tian, Tian, Min Bu, Xu Chen, Linli Ding, Yulan Yang, Jinhua Han, Xin-Hua Feng, et al. "The ZATT-TOP2A-PICH Axis Drives Extensive Replication Fork Reversal to Promote Genome Stability." Molecular Cell 81, no. 1 (January 2021): 198–211. http://dx.doi.org/10.1016/j.molcel.2020.11.007.

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40

Regairaz, Marie, Yong-Wei Zhang, Haiqing Fu, Keli K. Agama, Nalini Tata, Surbhi Agrawal, Mirit I. Aladjem, and Yves Pommier. "Mus81-mediated DNA cleavage resolves replication forks stalled by topoisomerase I–DNA complexes." Journal of Cell Biology 195, no. 5 (November 28, 2011): 739–49. http://dx.doi.org/10.1083/jcb.201104003.

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Deoxyribonucleic acid (DNA) topoisomerases are essential for removing the supercoiling that normally builds up ahead of replication forks. The camptothecin (CPT) Top1 (topoisomerase I) inhibitors exert their anticancer activity by reversibly trapping Top1–DNA cleavage complexes (Top1cc’s) and inducing replication-associated DNA double-strand breaks (DSBs). In this paper, we propose a new mechanism by which cells avoid Top1-induced replication-dependent DNA damage. We show that the structure-specific endonuclease Mus81-Eme1 is responsible for generating DSBs in response to Top1 inhibition and for allowing cell survival. We provide evidence that Mus81 cleaves replication forks rather than excises Top1cc’s. DNA combing demonstrated that Mus81 also allows efficient replication fork progression after CPT treatment. We propose that Mus81 cleaves stalled replication forks, which allows dissipation of the excessive supercoiling resulting from Top1 inhibition, spontaneous reversal of Top1cc, and replication fork progression.

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Neelsen, Kai J., Isabella M. Y. Zanini, Raquel Herrador, and Massimo Lopes. "Oncogenes induce genotoxic stress by mitotic processing of unusual replication intermediates." Journal of Cell Biology 200, no. 6 (March 11, 2013): 699–708. http://dx.doi.org/10.1083/jcb.201212058.

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Oncogene-induced DNA replication stress activates the DNA damage response (DDR), a crucial anticancer barrier. DDR inactivation in these conditions promotes genome instability and tumor progression, but the underlying molecular mechanisms are elusive. We found that overexpression of both Cyclin E and Cdc25A rapidly slowed down replication forks and induced fork reversal, suggestive of increased topological stress. Surprisingly, these phenotypes, per se, are neither associated with chromosomal breakage nor with significant DDR activation. Oncogene-induced DNA breakage and DDR activation instead occurred upon persistent G2/M arrest or, in a checkpoint-defective context, upon premature CDK1 activation. Depletion of MUS81, a cell cycle–regulated nuclease, markedly limited chromosomal breakage and led to further accumulation of reversed forks. We propose that nucleolytic processing of unusual replication intermediates mediates oncogene-induced genotoxicity and that limiting such processing to mitosis is a central anti-tumorigenic function of the DNA damage checkpoints.

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Bai, Gongshi, Chames Kermi, Henriette Stoy, Carl J. Schiltz, Julien Bacal, Angela M. Zaino, M. Kyle Hadden, Brandt F. Eichman, Massimo Lopes, and Karlene A. Cimprich. "HLTF Promotes Fork Reversal, Limiting Replication Stress Resistance and Preventing Multiple Mechanisms of Unrestrained DNA Synthesis." Molecular Cell 78, no. 6 (June 2020): 1237–51. http://dx.doi.org/10.1016/j.molcel.2020.04.031.

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Vujanovic, Marko, Jana Krietsch, Maria Chiara Raso, Nastassja Terraneo, Ralph Zellweger, Jonas A. Schmid, Angelo Taglialatela, et al. "Replication Fork Slowing and Reversal upon DNA Damage Require PCNA Polyubiquitination and ZRANB3 DNA Translocase Activity." Molecular Cell 67, no. 5 (September 2017): 882–90. http://dx.doi.org/10.1016/j.molcel.2017.08.010.

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Walker, John R., and Xu-Dong Zhu. "Role of Cockayne Syndrome Group B Protein in Replication Stress: Implications for Cancer Therapy." International Journal of Molecular Sciences 23, no. 18 (September 6, 2022): 10212. http://dx.doi.org/10.3390/ijms231810212.

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A variety of endogenous and exogenous insults are capable of impeding replication fork progression, leading to replication stress. Several SNF2 fork remodelers have been shown to play critical roles in resolving this replication stress, utilizing different pathways dependent upon the nature of the DNA lesion, location on the DNA, and the stage of the cell cycle, to complete DNA replication in a manner preserving genetic integrity. Under certain conditions, however, the attempted repair may lead to additional genetic instability. Cockayne syndrome group B (CSB) protein, a SNF2 chromatin remodeler best known for its role in transcription-coupled nucleotide excision repair, has recently been shown to catalyze fork reversal, a pathway that can provide stability of stalled forks and allow resumption of DNA synthesis without chromosome breakage. Prolonged stalling of replication forks may collapse to give rise to DNA double-strand breaks, which are preferentially repaired by homology-directed recombination. CSB plays a role in repairing collapsed forks by promoting break-induced replication in S phase and early mitosis. In this review, we discuss roles of CSB in regulating the sources of replication stress, replication stress response, as well as the implications of CSB for cancer therapy.

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Guarino, Estrella, Alfonso Jiménez-Sánchez, and Elena C. Guzmán. "Defective Ribonucleoside Diphosphate Reductase Impairs Replication Fork Progression in Escherichia coli." Journal of Bacteriology 189, no. 9 (February 23, 2007): 3496–501. http://dx.doi.org/10.1128/jb.01632-06.

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ABSTRACT The observed lengthening of the C period in the presence of a defective ribonucleoside diphosphate reductase has been assumed to be due solely to the low deoxyribonucleotide supply in the nrdA101 mutant strain. We show here that the nrdA101 mutation induces DNA double-strand breaks at the permissive temperature in a recB-deficient background, suggesting an increase in the number of stalled replication forks that could account for the slowing of replication fork progression observed in the nrdA101 strain in a Rec+ context. These DNA double-strand breaks require the presence of the Holliday junction resolvase RuvABC, indicating that they have been generated from stalled replication forks that were processed by the specific reaction named “replication fork reversal.” Viability results supported the occurrence of this process, as specific lethality was observed in the nrdA101 recB double mutant and was suppressed by the additional inactivation of ruvABC. None of these effects seem to be due to the limitation of the deoxyribonucleotide supply in the nrdA101 strain even at the permissive temperature, as we found the same level of DNA double-strand breaks in the nrdA + strain growing under limited (2-μg/ml) or under optimal (5-μg/ml) thymidine concentrations. We propose that the presence of an altered NDP reductase, as a component of the replication machinery, impairs the progression of the replication fork, contributing to the lengthening of the C period in the nrdA101 mutant at the permissive temperature.

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Aiello, Francesca Antonella, Anita Palma, Eva Malacaria, Li Zheng, Judith L. Campbell, Binghui Shen, Annapaola Franchitto, and Pietro Pichierri. "RAD51 and mitotic function of mus81 are essential for recovery from low-dose of camptothecin in the absence of the WRN exonuclease." Nucleic Acids Research 47, no. 13 (May 22, 2019): 6796–810. http://dx.doi.org/10.1093/nar/gkz431.

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Abstract Stabilization of stalled replication forks prevents excessive fork reversal or degradation, which can undermine genome integrity. The WRN protein is unique among the other human RecQ family members to possess exonuclease activity. However, the biological role of the WRN exonuclease is poorly defined. Recently, the WRN exonuclease has been linked to protection of stalled forks from degradation. Alternative processing of perturbed forks has been associated to chemoresistance of BRCA-deficient cancer cells. Thus, we used WRN exonuclease-deficiency as a model to investigate the fate of perturbed forks undergoing degradation, but in a BRCA wild-type condition. We find that, upon treatment with clinically-relevant nanomolar doses of the Topoisomerase I inhibitor camptothecin, loss of WRN exonuclease stimulates fork inactivation and accumulation of parental gaps, which engages RAD51. Such mechanism affects reinforcement of CHK1 phosphorylation and causes persistence of RAD51 during recovery from treatment. Notably, in WRN exonuclease-deficient cells, persistence of RAD51 correlates with elevated mitotic phosphorylation of MUS81 at Ser87, which is essential to prevent excessive mitotic abnormalities. Altogether, these findings indicate that aberrant fork degradation, in the presence of a wild-type RAD51 axis, stimulates RAD51-mediated post-replicative repair and engagement of the MUS81 complex to limit genome instability and cell death.

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Grompone, Gianfranco, Marie Seigneur, S. Dusko Ehrlich, and Bénédicte Michel. "Replication fork reversal in DNA polymerase III mutants of Escherichia coli: a role for the β clamp." Molecular Microbiology 44, no. 5 (May 23, 2002): 1331–39. http://dx.doi.org/10.1046/j.1365-2958.2002.02962.x.

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Pilzecker, Bas, Olimpia Alessandra Buoninfante, and Heinz Jacobs. "DNA damage tolerance in stem cells, ageing, mutagenesis, disease and cancer therapy." Nucleic Acids Research 47, no. 14 (June 28, 2019): 7163–81. http://dx.doi.org/10.1093/nar/gkz531.

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AbstractThe DNA damage response network guards the stability of the genome from a plethora of exogenous and endogenous insults. An essential feature of the DNA damage response network is its capacity to tolerate DNA damage and structural impediments during DNA synthesis. This capacity, referred to as DNA damage tolerance (DDT), contributes to replication fork progression and stability in the presence of blocking structures or DNA lesions. Defective DDT can lead to a prolonged fork arrest and eventually cumulate in a fork collapse that involves the formation of DNA double strand breaks. Four principal modes of DDT have been distinguished: translesion synthesis, fork reversal, template switching and repriming. All DDT modes warrant continuation of replication through bypassing the fork stalling impediment or repriming downstream of the impediment in combination with filling of the single-stranded DNA gaps. In this way, DDT prevents secondary DNA damage and critically contributes to genome stability and cellular fitness. DDT plays a key role in mutagenesis, stem cell maintenance, ageing and the prevention of cancer. This review provides an overview of the role of DDT in these aspects.

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Gold, Michaela A., Jenna M. Whalen, Karine Freon, Zixin Hong, Ismail Iraqui, Sarah A. E. Lambert, and Catherine H. Freudenreich. "Restarted replication forks are error-prone and cause CAG repeat expansions and contractions." PLOS Genetics 17, no. 10 (October 21, 2021): e1009863. http://dx.doi.org/10.1371/journal.pgen.1009863.

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Disease-associated trinucleotide repeats form secondary DNA structures that interfere with replication and repair. Replication has been implicated as a mechanism that can cause repeat expansions and contractions. However, because structure-forming repeats are also replication barriers, it has been unclear whether the instability occurs due to slippage during normal replication progression through the repeat, slippage or misalignment at a replication stall caused by the repeat, or during subsequent replication of the repeat by a restarted fork that has altered properties. In this study, we have specifically addressed the fidelity of a restarted fork as it replicates through a CAG/CTG repeat tract and its effect on repeat instability. To do this, we used a well-characterized site-specific replication fork barrier (RFB) system in fission yeast that creates an inducible and highly efficient stall that is known to restart by recombination-dependent replication (RDR), in combination with long CAG repeat tracts inserted at various distances and orientations with respect to the RFB. We find that replication by the restarted fork exhibits low fidelity through repeat sequences placed 2–7 kb from the RFB, exhibiting elevated levels of Rad52- and Rad8ScRad5/HsHLTF-dependent instability. CAG expansions and contractions are not elevated to the same degree when the tract is just in front or behind the barrier, suggesting that the long-traveling Polδ-Polδ restarted fork, rather than fork reversal or initial D-loop synthesis through the repeat during stalling and restart, is the greatest source of repeat instability. The switch in replication direction that occurs due to replication from a converging fork while the stalled fork is held at the barrier is also a significant contributor to the repeat instability profile. Our results shed light on a long-standing question of how fork stalling and RDR contribute to expansions and contractions of structure-forming trinucleotide repeats, and reveal that tolerance to replication stress by fork restart comes at the cost of increased instability of repetitive sequences.

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Arzuza, Luis C. C., Victor Vega, Victor M. Prida, Karoline O. Moura, Kleber R. Pirota, and Fanny Béron. "Single Diameter Modulation Effects on Ni Nanowire Array Magnetization Reversal." Nanomaterials 11, no. 12 (December 16, 2021): 3403. http://dx.doi.org/10.3390/nano11123403.

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Geometrically modulated magnetic nanowires are a simple yet efficient strategy to modify the magnetic domain wall propagation since a simple diameter modulation can achieve its pinning during the nanowire magnetization reversal. However, in dense systems of parallel nanowires, the stray fields arising at the diameter interface can interfere with the domain wall propagation in the neighboring nanowires. Therefore, the magnetic behavior of diameter-modulated nanowire arrays can be quite complex and depending on both short and long-range interaction fields, as well as the nanowire geometric dimensions. We applied the first-order reversal curve (FORC) method to bi-segmented Ni nanowire arrays varying the wide segment (45–65 nm diameter, 2.5–10.0 μm length). The FORC results indicate a magnetic behavior modification depending on its length/diameter aspect ratio. The distributions either exhibit a strong extension along the coercivity axis or a main distribution finishing by a fork feature, whereas the extension greatly reduces in amplitude. With the help of micromagnetic simulations, we propose that a low aspect ratio stabilizes pinned domain walls at the diameter modulation during the magnetization reversal. In this case, long-range axial interaction fields nucleate a domain wall at the nanowire extremities, while short-range ones could induce a nucleation at the diameter interface. However, regardless of the wide segment aspect ratio, the magnetization reversal is governed by the local radial stray fields of the modulation near null magnetization. Our findings demonstrate the capacity of distinguishing between complex magnetic behaviors involving convoluted interaction fields.

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