Mehta, A. & Haber, J. E. Sources of DNA double-strand breaks and models of recombinational DNA repair. Cold Spring Harb. Perspect. Biol. 6, a016428 (2014).
Google Scholar
Ensminger, M. & Lobrich, M. One end to rule them all: non-homologous end-joining and homologous recombination at DNA double-strand breaks. Br. J. Radiol. 93, 20191054 (2020).
Google Scholar
Scully, R., Panday, A., Elango, R. & Willis, N. A. DNA double-strand break repair-pathway choice in somatic mammalian cells. Nat. Rev. Mol. Cell Biol. 20, 698–714 (2019).
Google Scholar
Chang, H. H. Y., Pannunzio, N. R., Adachi, N. & Lieber, M. R. Non-homologous DNA end joining and alternative pathways to double-strand break repair. Nat. Rev. Mol. Cell Biol. 18, 495–506 (2017).
Google Scholar
Pannunzio, N. R., Watanabe, G. & Lieber, M. R. Nonhomologous DNA end-joining for repair of DNA double-strand breaks. J. Biol. Chem. 293, 10512–10523 (2018).
Google Scholar
Zhao, W., Wiese, C., Kwon, Y., Hromas, R. & Sung, P. The BRCA tumor suppressor network in chromosome damage repair by homologous recombination. Annu. Rev. Biochem. 88, 221–245 (2019).
Google Scholar
Tarsounas, M. & Sung, P. The antitumorigenic roles of BRCA1–BARD1 in DNA repair and replication. Nat. Rev. Mol. Cell Biol. 21, 284–299 (2020).
Google Scholar
DeFazio, L. G., Stansel, R. M., Griffith, J. D. & Chu, G. Synapsis of DNA ends by DNA-dependent protein kinase. EMBO J. 21, 3192–3200 (2002).
Google Scholar
Myler, L. R. et al. Single-molecule imaging reveals how MRE11–RAD50–NBS1 initiates DNA break repair. Mol. Cell 67, 891–898.e4 (2017).
Google Scholar
Anand, R., Ranjha, L., Cannavo, E. & Cejka, P. Phosphorylated CtIP functions as a co-factor of the MRE11–RAD50–NBS1 endonuclease in DNA end resection. Mol. Cell 64, 940–950 (2016). This biochemical study established phosphorylated CtIP as a cofactor that activates the MRN endonuclease, clarifying how short-range resection is initiated at blocked DNA ends.
Google Scholar
Cannavo, E. & Cejka, P. Sae2 promotes dsDNA endonuclease activity within MRE11–RAD50–XRS2 to resect DNA breaks. Nature 514, 122–125 (2014).
Google Scholar
Langerak, P., Mejia-Ramirez, E., Limbo, O. & Russell, P. Release of Ku and MRN from DNA ends by Mre11 nuclease activity and Ctp1 is required for homologous recombination repair of double-strand breaks. PLoS Genet. 7, e1002271 (2011).
Google Scholar
Chanut, P., Britton, S., Coates, J., Jackson, S. P. & Calsou, P. Coordinated nuclease activities counteract Ku at single-ended DNA double-strand breaks. Nat. Commun. 7, 12889 (2016).
Google Scholar
Zhu, Z., Chung, W. H., Shim, E. Y., Lee, S. E. & Ira, G. Sgs1 helicase and two nucleases Dna2 and Exo1 resect DNA double-strand break ends. Cell 134, 981–994 (2008). This foundational work defined the two principal long-range resection routes — Exo1 and Sgs1–Dna2 — downstream of the MRE11–RAD50–XRS2 (MRX) complex in budding yeast.
Google Scholar
Niu, H. et al. Mechanism of the ATP-dependent DNA end-resection machinery from Saccharomyces cerevisiae. Nature 467, 108–111 (2010).
Google Scholar
Toczylowski, T. & Yan, H. Mechanistic analysis of a DNA end processing pathway mediated by the Xenopus Werner syndrome protein. J. Biol. Chem. 281, 33198–33205 (2006).
Google Scholar
Sturzenegger, A. et al. DNA2 cooperates with the WRN and BLM RecQ helicases to mediate long-range DNA end resection in human cells. J. Biol. Chem. 289, 27314–27326 (2014).
Google Scholar
Salunkhe, S. et al. Promotion of DNA end resection by BRCA1–BARD1 in homologous recombination. Nature 634, 482–491 (2024). Using reconstituted and single-molecule systems, this study showed that BRCA1–BARD1 directly stimulates EXO1-dependent, BLM–DNA2-dependent and WRN–DNA2-dependent long-range resection.
Google Scholar
Ceppi, I. et al. Mechanism of BRCA1–BARD1 function in DNA end resection and DNA protection. Nature 634, 492–500 (2024). This biochemical study established that BRCA1–BARD1 directly promotes long-range end resection while also protecting stalled replication-fork DNA, unifying two major genome-maintenance functions of the complex.
Google Scholar
Cejka, P. & Symington, L. S. DNA end resection: mechanism and control. Annu. Rev. Genet. 55, 285–307 (2021).
Google Scholar
Zhao, F. et al. ASTE1 promotes shieldin-complex-mediated DNA repair by attenuating end resection. Nat. Cell Biol. 23, 894–904 (2021).
Google Scholar
Mirman, Z., Sasi, N. K., King, A., Chapman, J. R. & de Lange, T. 53BP1–shieldin-dependent DSB processing in BRCA1-deficient cells requires CST–Polα–primase fill-in synthesis. Nat. Cell Biol. 24, 51–61 (2022).
Google Scholar
Ceccaldi, R. & Cejka, P. Mechanisms and regulation of DNA end resection in the maintenance of genome stability. Nat. Rev. Mol. Cell Biol. 26, 586–599 (2025).
Google Scholar
Bunting, S. F. et al. 53BP1 inhibits homologous recombination in Brca1-deficient cells by blocking resection of DNA breaks. Cell 141, 243–254 (2010). This landmark genetic study showed that 53BP1 loss restores end resection and HR in BRCA1-deficient cells, establishing the 53BP1–BRCA1 antagonism at the heart of repair-pathway choice.
Google Scholar
Mirman, Z. & de Lange, T. 53BP1: a DSB escort. Genes Dev. 34, 7–23 (2020).
Google Scholar
Setiaputra, D. & Durocher, D. Shieldin — the protector of DNA ends. EMBO Rep. 20, e47560 (2019).
Google Scholar
Noordermeer, S. M. et al. The shieldin complex mediates 53BP1-dependent DNA repair. Nature 560, 117–121 (2018).
Google Scholar
Mirman, Z. et al. 53BP1–RIF1–shieldin counteracts DSB resection through CST- and Polα-dependent fill-in. Nature 560, 112–116 (2018). This study connected the 53BP1–RIF1–shieldin axis to CST–Polα–primase-mediated fill-in synthesis, revealing an active mechanism that counteracts resection rather than merely shielding DNA ends.
Google Scholar
Dev, H. et al. Shieldin complex promotes DNA end-joining and counters homologous recombination in BRCA1-null cells. Nat. Cell Biol. 20, 954–965 (2018).
Google Scholar
Ghezraoui, H. et al. 53BP1 cooperation with the REV7-shieldin complex underpins DNA structure-specific NHEJ. Nature 560, 122–127 (2018).
Google Scholar
Gupta, R. et al. DNA repair network analysis reveals shieldin as a key regulator of NHEJ and PARP inhibitor sensitivity. Cell 173, 972–988.e23 (2018).
Google Scholar
Findlay, S. et al. SHLD2/FAM35A co-operates with REV7 to coordinate DNA double-strand break repair pathway choice. EMBO J. 37, e100158 (2018).
Google Scholar
Xu, G. et al. REV7 counteracts DNA double-strand break resection and affects PARP inhibition. Nature 521, 541–544 (2015).
Google Scholar
Barazas, M. et al. The CST complex mediates end protection at double-strand breaks and promotes PARP inhibitor sensitivity in BRCA1-deficient cells. Cell Rep. 23, 2107–2118 (2018).
Google Scholar
Callen, E. et al. 53BP1 enforces distinct pre- and post-resection blocks on homologous recombination. Mol. Cell 77, 26–38.e7 (2020).
Google Scholar
Cruz-Garcia, A., Lopez-Saavedra, A. & Huertas, P. BRCA1 accelerates CtIP-mediated DNA-end resection. Cell Rep. 9, 451–459 (2014).
Google Scholar
Farmer, H. et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434, 917–921 (2005). This landmark study demonstrated that BRCA1-deficient and BRCA2-deficient cells are selectively killed by PARP inhibition, providing a mechanistic foundation for PARP inhibitor therapy.
Google Scholar
Bryant, H. E. et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434, 913–917 (2005). Published alongside Farmer et al. (2005), this study independently demonstrated the exquisite sensitivity of BRCA2-deficient cells to PARP inhibition, launching the synthetic-lethality paradigm that transformed BRCA-targeted therapy.
Google Scholar
Lord, C. J. & Ashworth, A. PARP inhibitors: synthetic lethality in the clinic. Science 355, 1152–1158 (2017).
Google Scholar
Li, X. & Zou, L. BRCAness, DNA gaps, and gain and loss of PARP inhibitor-induced synthetic lethality. J. Clin. Invest. 134, e181062 (2024).
Google Scholar
Rogers, C. M. et al. CTC1–STN1–TEN1 controls DNA break repair pathway choice via DNA end resection blockade. Science 388, 881–888 (2025). This study demonstrated that CST directly blocks both EXO1 and BLM–DNA2 resection, establishing nuclease inhibition as a second CST mechanism alongside Polα–primase-dependent fill-in.
Google Scholar
Britton, S. et al. DNA damage triggers SAF-A and RNA biogenesis factors exclusion from chromatin coupled to R-loops removal. Nucleic Acids Res. 42, 9047–9062 (2014).
Google Scholar
Ohle, C. et al. Transient RNA–DNA hybrids are required for efficient double-strand break repair. Cell 167, 1001–1013.e7 (2016). This work demonstrated that RNA–DNA hybrids form transiently at DSBs and that their timely resolution is required for efficient HR, establishing RNA as an active component of break repair.
Google Scholar
Li, L. et al. DEAD box 1 facilitates removal of RNA and homologous recombination at DNA double-strand breaks. Mol. Cell Biol. 36, 2794–2810 (2016).
Google Scholar
Biehs, R. et al. DNA double-strand break resection occurs during non-homologous end joining in G1 but is distinct from resection during homologous recombination. Mol. Cell 65, 671–684.e5 (2017).
Google Scholar
Lazzaro, F. et al. Histone methyltransferase Dot1 and Rad9 inhibit single-stranded DNA accumulation at DSBs and uncapped telomeres. EMBO J. 27, 1502–1512 (2008).
Google Scholar
Lydall, D. & Weinert, T. Yeast checkpoint genes in DNA damage processing: implications for repair and arrest. Science 270, 1488–1491 (1995).
Google Scholar
Densham, R. M. et al. Human BRCA1–BARD1 ubiquitin ligase activity counteracts chromatin barriers to DNA resection. Nat. Struct. Mol. Biol. 23, 647–655 (2016).
Google Scholar
Isono, M. et al. BRCA1 directs the repair pathway to homologous recombination by promoting 53BP1 dephosphorylation. Cell Rep. 18, 520–532 (2017).
Google Scholar
Chapman, J. R., Sossick, A. J., Boulton, S. J. & Jackson, S. P. BRCA1-associated exclusion of 53BP1 from DNA damage sites underlies temporal control of DNA repair. J. Cell Sci. 125, 3529–3534 (2012).
Google Scholar
Jaspers, J. E. et al. Loss of 53BP1 causes PARP inhibitor resistance in BRCA1-mutated mouse mammary tumors. Cancer Discov. 3, 68–81 (2013).
Google Scholar
Bouwman, P. et al. 53BP1 loss rescues BRCA1 deficiency and is associated with triple-negative and BRCA-mutated breast cancers. Nat. Struct. Mol. Biol. 17, 688–695 (2010).
Google Scholar
Mailand, N. et al. RNF8 ubiquitylates histones at DNA double-strand breaks and promotes assembly of repair proteins. Cell 131, 887–900 (2007).
Google Scholar
Doil, C. et al. RNF168 binds and amplifies ubiquitin conjugates on damaged chromosomes to allow accumulation of repair proteins. Cell 136, 435–446 (2009).
Google Scholar
Gatti, M. et al. RNF168 promotes noncanonical K27 ubiquitination to signal DNA damage. Cell Rep. 10, 226–238 (2015).
Google Scholar
Paquin, K. L. & Howlett, N. G. Understanding the histone DNA repair code: H4K20me2 makes its mark. Mol. Cancer Res. 16, 1335–1345 (2018).
Google Scholar
Wilson, M. D. et al. The structural basis of modified nucleosome recognition by 53BP1. Nature 536, 100–103 (2016).
Google Scholar
Becker, J. R. et al. BARD1 reads H2A lysine 15 ubiquitination to direct homologous recombination. Nature 596, 433–437 (2021). This study identified BARD1 as a reader of H2AK15ub and unmethylated H4K20 in post-replicative chromatin, explaining how BRCA1–BARD1 is targeted to HR-competent breaks and antagonizes 53BP1.
Google Scholar
Fradet-Turcotte, A. et al. 53BP1 is a reader of the DNA-damage-induced H2A Lys 15 ubiquitin mark. Nature 499, 50–54 (2013).
Google Scholar
Michelena, J., Pellegrino, S., Spegg, V. & Altmeyer, M. Replicated chromatin curtails 53BP1 recruitment in BRCA1-proficient and BRCA1-deficient cells. Life Sci. Alliance 4, e202101023 (2021).
Google Scholar
Pellegrino, S., Michelena, J., Teloni, F., Imhof, R. & Altmeyer, M. Replication-coupled dilution of H4K20me2 guides 53BP1 to pre-replicative chromatin. Cell Rep. 19, 1819–1831 (2017).
Google Scholar
Panier, S. & Boulton, S. J. Double-strand break repair: 53BP1 comes into focus. Nat. Rev. Mol. Cell Biol. 15, 7–18 (2014).
Google Scholar
Rass, E., Willaume, S. & Bertrand, P. 53BP1: keeping it under control, even at a distance from DNA damage. Genes 13, 2390 (2022).
Google Scholar
Setiaputra, D. et al. RIF1 acts in DNA repair through phosphopeptide recognition of 53BP1. Mol. Cell 82, 1359–1371.e9 (2022).
Google Scholar
Chapman, J. R. et al. RIF1 is essential for 53BP1-dependent nonhomologous end joining and suppression of DNA double-strand break resection. Mol. Cell 49, 858–871 (2013).
Google Scholar
Escribano-Diaz, C. et al. A cell cycle-dependent regulatory circuit composed of 53BP1-RIF1 and BRCA1-CtIP controls DNA repair pathway choice. Mol. Cell 49, 872–883 (2013). This study defined the cell-cycle-regulated 53BP1–RIF1 versus BRCA1–CtIP circuit that couples resection control to DSB repair-pathway choice.
Google Scholar
Di Virgilio, M. et al. Rif1 prevents resection of DNA breaks and promotes immunoglobulin class switching. Science 339, 711–715 (2013).
Google Scholar
Bakr, A. et al. Impaired 53BP1/RIF1 DSB mediated end-protection stimulates CtIP-dependent end resection and switches the repair to PARP1-dependent end joining in G1. Oncotarget 7, 57679–57693 (2016).
Google Scholar
Isobe, S. Y. et al. Protein phosphatase 1 acts as a RIF1 effector to suppress DSB resection prior to Shieldin action. Cell Rep. 36, 109383 (2021).
Google Scholar
Becker, J. R. et al. The ASCIZ–DYNLL1 axis promotes 53BP1-dependent non-homologous end joining and PARP inhibitor sensitivity. Nat. Commun. 9, 5406 (2018).
Google Scholar
West, K. L. et al. LC8/DYNLL1 is a 53BP1 effector and regulates checkpoint activation. Nucleic Acids Res. 47, 6236–6249 (2019).
Google Scholar
He, Y. J. et al. DYNLL1 binds to MRE11 to limit DNA end resection in BRCA1-deficient cells. Nature 563, 522–526 (2018).
Google Scholar
Swift, M. L. et al. Dynamics of the DYNLL1–MRE11 complex regulate DNA end resection and recruitment of Shieldin to DSBs. Nat. Struct. Mol. Biol. 30, 1456–1467 (2023).
Google Scholar
Lim, C. J. Telomere C-strand fill-in machinery: new insights into the human CST–DNA polymerase α-primase structures and functions. Subcell. Biochem. 104, 73–100 (2024).
Google Scholar
Wang, F. et al. Human CST has independent functions during telomere duplex replication and C-strand fill-in. Cell Rep. 2, 1096–1103 (2012).
Google Scholar
Miyake, Y. et al. RPA-like mammalian Ctc1–Stn1–Ten1 complex binds to single-stranded DNA and protects telomeres independently of the Pot1 pathway. Mol. Cell 36, 193–206 (2009).
Google Scholar
Lyu, X. et al. Human CST complex protects stalled replication forks by directly blocking MRE11 degradation of nascent-strand DNA. EMBO J. 40, e103654 (2021).
Google Scholar
Hom, R. A. & Wuttke, D. S. Human CST prefers G-rich but not necessarily telomeric sequences. Biochemistry 56, 4210–4218 (2017).
Google Scholar
Sifri, C., Hoeg, L., Durocher, D. & Setiaputra, D. An AlphaFold2 map of the 53BP1 pathway identifies a direct SHLD3–RIF1 interaction critical for shieldin activity. EMBO Rep. 24, e56834 (2023).
Google Scholar
Lim, C. J. et al. The structure of human CST reveals a decameric assembly bound to telomeric DNA. Science 368, 1081–1085 (2020).
Google Scholar
Pavani, R. et al. Structure and repair of replication-coupled DNA breaks. Science 385, eado3867 (2024).
Google Scholar
Moynahan, M. E., Chiu, J. W., Koller, B. H. & Jasin, M. BRCA1 controls homology-directed DNA repair. Mol. Cell 4, 511–518 (1999). This foundational reporter study established that BRCA1 is directly required for homology-directed repair of chromosomal DSBs.
Google Scholar
Sherker, A. et al. Two redundant ubiquitin-dependent pathways of BRCA1 localization to DNA damage sites. EMBO Rep. 22, e53679 (2021).
Google Scholar
Sobhian, B. et al. RAP80 targets BRCA1 to specific ubiquitin structures at DNA damage sites. Science 316, 1198–1202 (2007).
Google Scholar
Kim, H., Chen, J. & Yu, X. Ubiquitin-binding protein RAP80 mediates BRCA1-dependent DNA damage response. Science 316, 1202–1205 (2007).
Google Scholar
Chen, L., Nievera, C. J., Lee, A. Y. & Wu, X. Cell cycle-dependent complex formation of BRCA1.CtIP.MRN is important for DNA double-strand break repair. J. Biol. Chem. 283, 7713–7720 (2008).
Google Scholar
Wang, M. et al. Crucial roles of the BRCA1–BARD1 E3 ubiquitin ligase activity in homology-directed DNA repair. Mol. Cell 83, 3679–3691.e8 (2023).
Google Scholar
Ceppi, I. et al. CtIP promotes the motor activity of DNA2 to accelerate long-range DNA end resection. Proc. Natl Acad. Sci. USA 117, 8859–8869 (2020).
Google Scholar
Feng, L. et al. Cell cycle-dependent inhibition of 53BP1 signaling by BRCA1. Cell Discov. 1, 15019 (2015).
Google Scholar
Kakarougkas, A. et al. Co-operation of BRCA1 and POH1 relieves the barriers posed by 53BP1 and RAP80 to resection. Nucleic Acids Res. 41, 10298–10311 (2013).
Google Scholar
Xu, Y. et al. 53BP1 and BRCA1 control pathway choice for stalled replication restart. eLife 6, e30523 (2017).
Google Scholar
Shah, S. B. et al. 53BP1 deficiency leads to hyperrecombination using break-induced replication (BIR). Nat. Commun. 15, 8648 (2024).
Google Scholar
Daza-Martin, M. et al. Isomerization of BRCA1–BARD1 promotes replication fork protection. Nature 571, 521–527 (2019).
Google Scholar
Marnef, A. & Legube, G. R-loops as Janus-faced modulators of DNA repair. Nat. Cell Biol. 23, 305–313 (2021).
Google Scholar
Cohen, S. et al. Senataxin resolves RNA:DNA hybrids forming at DNA double-strand breaks to prevent translocations. Nat. Commun. 9, 533 (2018).
Google Scholar
Rawal, C. C. et al. Senataxin ortholog Sen1 limits DNA:RNA hybrid accumulation at DNA double-strand breaks to control end resection and repair fidelity. Cell Rep. 31, 107603 (2020).
Google Scholar
Ortega, P., Merida-Cerro, J. A., Rondon, A. G., Gomez-Gonzalez, B. & Aguilera, A. DNA–RNA hybrids at DSBs interfere with repair by homologous recombination. eLife 10, e69881 (2021).
Google Scholar
Michelini, F. et al. From “cellular” RNA to “smart” RNA: multiple roles of RNA in genome stability and beyond. Chem. Rev. 118, 4365–4403 (2018).
Google Scholar
Michelini, F. et al. Damage-induced lncRNAs control the DNA damage response through interaction with DDRNAs at individual double-strand breaks. Nat. Cell Biol. 19, 1400–1411 (2017).
Google Scholar
Lu, Y., Storici, F. & Jeon, Y. The multiple layers of RNA response in double-strand break repair. Exp. Mol. Med. 57, 2429–2439 (2025).
Google Scholar
Jalan, M. et al. RNA transcripts serve as a template for double-strand break repair in human cells. Nat. Commun. 16, 4349 (2025).
Google Scholar
Yang, Y. G. & Qi, Y. RNA-directed repair of DNA double-strand breaks. DNA Repair 32, 82–85 (2015).
Google Scholar
Crossley, M. P., Bocek, M. & Cimprich, K. A. R-loops as cellular regulators and genomic threats. Mol. Cell 73, 398–411 (2019).
Google Scholar
Skourti-Stathaki, K. & Proudfoot, N. J. A double-edged sword: R loops as threats to genome integrity and powerful regulators of gene expression. Genes Dev. 28, 1384–1396 (2014).
Google Scholar
Pessina, F. et al. Functional transcription promoters at DNA double-strand breaks mediate RNA-driven phase separation of damage-response factors. Nat. Cell Biol. 21, 1286–1299 (2019).
Google Scholar
Sharma, S. et al. MRE11–RAD50–NBS1 complex is sufficient to promote transcription by RNA polymerase II at double-strand breaks by melting DNA ends. Cell Rep. 34, 108565 (2021).
Google Scholar
Liu, S. et al. RNA polymerase III is required for the repair of DNA double-strand breaks by homologous recombination. Cell 184, 1314–1329.e10 (2021).
Google Scholar
Saur, F. et al. Transcriptional repression facilitates RNA:DNA hybrid accumulation at DNA double-strand breaks. Nat. Cell Biol. 27, 992–1005 (2025).
Google Scholar
Kruhlak, M. et al. The ATM repair pathway inhibits RNA polymerase I transcription in response to chromosome breaks. Nature 447, 730–734 (2007).
Google Scholar
Shanbhag, N. M., Rafalska-Metcalf, I. U., Balane-Bolivar, C., Janicki, S. M. & Greenberg, R. A. ATM-dependent chromatin changes silence transcription in cis to DNA double-strand breaks. Cell 141, 970–981 (2010).
Google Scholar
Pankotai, T., Bonhomme, C., Chen, D. & Soutoglou, E. DNAPKcs-dependent arrest of RNA polymerase II transcription in the presence of DNA breaks. Nat. Struct. Mol. Biol. 19, 276–282 (2012).
Google Scholar
Awwad, S. W., Abu-Zhayia, E. R., Guttmann-Raviv, N. & Ayoub, N. NELF-E is recruited to DNA double-strand break sites to promote transcriptional repression and repair. EMBO Rep. 18, 745–764 (2017).
Google Scholar
Tan-Wong, S. M., Dhir, S. & Proudfoot, N. J. R-loops promote antisense transcription across the mammalian genome. Mol. Cell 76, 600–616.e6 (2019).
Google Scholar
Yasuhara, T. et al. Human Rad52 promotes XPG-mediated R-loop processing to initiate transcription-associated homologous recombination repair. Cell 175, 558–570.e11 (2018).
Google Scholar
Ouyang, J. et al. RNA transcripts stimulate homologous recombination by forming DR-loops. Nature 594, 283–288 (2021). This study discovered DR-loops — three-stranded intermediates containing DNA–DNA and RNA–DNA hybrids — and showed how RNA transcripts can stimulate homologous recombination.
Google Scholar
Mazina, O. M. et al. Replication protein A binds RNA and promotes R-loop formation. J. Biol. Chem. 295, 14203–14213 (2020).
Google Scholar
Nguyen, H. D. et al. Functions of replication protein A as a sensor of R loops and a regulator of RNaseH1. Mol. Cell 65, 832–847.e4 (2017).
Google Scholar
Hatchi, E. et al. BRCA1 recruitment to transcriptional pause sites is required for R-loop-driven DNA damage repair. Mol. Cell 57, 636–647 (2015).
Google Scholar
Dutta, A. et al. Resolution of R-loops and transcription-replication conflicts by SETX–BRCA1–BARD1 complex. Nat. Struct. Mol. Biol. 33, 615–630 (2026).
Google Scholar
D’Alessandro, G. et al. BRCA2 controls DNA:RNA hybrid level at DSBs by mediating RNase H2 recruitment. Nat. Commun. 9, 5376 (2018).
Google Scholar
Bhatia, V. et al. BRCA2 prevents R-loop accumulation and associates with TREX-2 mRNA export factor PCID2. Nature 511, 362–365 (2014).
Google Scholar
Welty, S. et al. RAD52 is required for RNA-templated recombination repair in post-mitotic neurons. J. Biol. Chem. 293, 1353–1362 (2018).
Google Scholar
Skourti-Stathaki, K., Proudfoot, N. J. & Gromak, N. Human senataxin resolves RNA/DNA hybrids formed at transcriptional pause sites to promote Xrn2-dependent termination. Mol. Cell 42, 794–805 (2011).
Google Scholar
Hasanova, Z., Klapstova, V., Porrua, O., Stefl, R. & Sebesta, M. Human senataxin is a bona fide R-loop resolving enzyme and transcription termination factor. Nucleic Acids Res. 51, 2818–2837 (2023).
Google Scholar
Li, L., Monckton, E. A. & Godbout, R. A role for DEAD Box 1 at DNA double-strand breaks. Mol. Cell Biol. 28, 6413–6425 (2008).
Google Scholar
Sakasai, R. et al. Aquarius is required for proper CtIP expression and homologous recombination repair. Sci. Rep. 7, 13808 (2017).
Google Scholar
Yang, S., Winstone, L., Mondal, S. & Wu, Y. Helicases in R-loop formation and resolution. J. Biol. Chem. 299, 105307 (2023).
Google Scholar
Yu, Z. et al. DDX5 resolves R-loops at DNA double-strand breaks to promote DNA repair and avoid chromosomal deletions. NAR Cancer 2, zcaa028 (2020).
Google Scholar
Matsui, M. et al. USP42 enhances homologous recombination repair by promoting R-loop resolution with a DNA–RNA helicase DHX9. Oncogenesis 9, 60 (2020).
Google Scholar
Harvey-Jones, E. et al. Longitudinal profiling identifies co-occurring BRCA1/2 reversions, TP53BP1, RIF1 and PAXIP1 mutations in PARP inhibitor-resistant advanced breast cancer. Ann. Oncol. 35, 364–380 (2024). This longitudinal clinical-genomic study showed that BRCA1 and BRCA2 reversions as well as alterations in TP53BP1, RIF1 and PAXIP1 can co-occur in PARPi resistance, revealing polyclonal and mechanistically diverse evolution in patients.
Google Scholar
Lheureux, S. et al. Identifying mechanisms of resistance by circulating tumor DNA in EVOLVE, a phase II trial of cediranib plus olaparib for ovarian cancer at time of PARP inhibitor progression. Clin. Cancer Res. 29, 3706–3716 (2023).
Google Scholar
Hurley, R. M. et al. 53BP1 as a potential predictor of response in PARP inhibitor-treated homologous recombination-deficient ovarian cancer. Gynecol. Oncol. 153, 127–134 (2019).
Google Scholar
Waks, A. G. et al. Reversion and non-reversion mechanisms of resistance to PARP inhibitor or platinum chemotherapy in BRCA1/2-mutant metastatic breast cancer. Ann. Oncol. 31, 590–598 (2020).
Google Scholar
Barber, L. J. et al. Secondary mutations in BRCA2 associated with clinical resistance to a PARP inhibitor. J. Pathol. 229, 422–429 (2013).
Google Scholar
Dhillon, K. K., Swisher, E. M. & Taniguchi, T. Secondary mutations of BRCA1/2 and drug resistance. Cancer Sci. 102, 663–669 (2011).
Google Scholar
Kondrashova, O. et al. Secondary somatic mutations restoring RAD51C and RAD51D associated with acquired resistance to the PARP inhibitor rucaparib in high-grade ovarian carcinoma. Cancer Discov. 7, 984–998 (2017).
Google Scholar
Lin, K. K. et al. BRCA reversion mutations in circulating tumor DNA predict primary and acquired resistance to the PARP inhibitor rucaparib in high-grade ovarian carcinoma. Cancer Discov. 9, 210–219 (2019).
Google Scholar
Quigley, D. et al. Analysis of circulating cell-free DNA identifies multiclonal heterogeneity of BRCA2 reversion mutations associated with resistance to PARP inhibitors. Cancer Discov. 7, 999–1005 (2017).
Google Scholar
Sakai, W. et al. Functional restoration of BRCA2 protein by secondary BRCA2 mutations in BRCA2-mutated ovarian carcinoma. Cancer Res. 69, 6381–6386 (2009).
Google Scholar
Sakai, W. et al. Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers. Nature 451, 1116–1120 (2008).
Google Scholar
Weigelt, B. et al. Diverse BRCA1 and BRCA2 reversion mutations in circulating cell-free DNA of therapy-resistant breast or ovarian cancer. Clin. Cancer Res. 23, 6708–6720 (2017).
Google Scholar
Patch, A. M. et al. Whole-genome characterization of chemoresistant ovarian cancer. Nature 521, 489–494 (2015).
Google Scholar
Bouwman, P. & Jonkers, J. Molecular pathways: how can BRCA-mutated tumors become resistant to PARP inhibitors? Clin. Cancer Res. 20, 540–547 (2014).
Google Scholar
Mitri, Z., Goodyear, S. M. & Mills, G. Strategies for the prevention or reversal of PARP inhibitor resistance. Expert Rev. Anticancer Ther. 24, 959–975 (2024).
Google Scholar
Pennington, K. P. et al. 53BP1 expression in sporadic and inherited ovarian carcinoma: relationship to genetic status and clinical outcomes. Gynecol. Oncol. 128, 493–499 (2013).
Google Scholar
Bazan Russo, T. D. et al. Polθ: emerging synthetic lethal partner in homologous recombination-deficient tumors. Cancer Gene Ther. 31, 1619–1631 (2024).
Google Scholar
Ceccaldi, R. et al. Homologous-recombination-deficient tumours are dependent on Polθ-mediated repair. Nature 518, 258–262 (2015). This study established Polθ-mediated end joining as a survival dependency of HR-deficient tumours, revealing a second clinically actionable synthetic-lethal vulnerability beyond PARP.
Google Scholar
Wu, J., Xu, Y. & Xiao, L. DNA polymerase theta in cancer therapy: mechanism of action and modulator development. Biochem. Pharmacol. 243, 117513 (2026).
Google Scholar
Zhou, J. et al. A first-in-class polymerase theta inhibitor selectively targets homologous-recombination-deficient tumors. Nat. Cancer 2, 598–610 (2021).
Google Scholar
Mateos-Gomez, P. A. et al. Mammalian polymerase θ promotes alternative NHEJ and suppresses recombination. Nature 518, 254–257 (2015).
Google Scholar
Zimmermann, M. & de Lange, T. 53BP1: pro choice in DNA repair. Trends Cell Biol. 24, 108–117 (2014).
Google Scholar
Zimmermann, M., Lottersberger, F., Buonomo, S. B., Sfeir, A. & de Lange, T. 53BP1 regulates DSB repair using Rif1 to control 5’ end resection. Science 339, 700–704 (2013).
Google Scholar
Feng, L., Fong, K. W., Wang, J., Wang, W. & Chen, J. RIF1 counteracts BRCA1-mediated end resection during DNA repair. J. Biol. Chem. 288, 11135–11143 (2013).
Google Scholar
Jurado, S. et al. The Zinc-finger protein ASCIZ regulates B cell development via DYNLL1 and Bim. J. Exp. Med. 209, 1629–1639 (2012).
Google Scholar
Zhao, F., Kim, W., Kloeber, J. A. & Lou, Z. DNA end resection and its role in DNA replication and DSB repair choice in mammalian cells. Exp. Mol. Med. 52, 1705–1714 (2020).
Google Scholar
Sun, J., Lee, K. J., Davis, A. J. & Chen, D. J. Human Ku70/80 protein blocks exonuclease 1-mediated DNA resection in the presence of human Mre11 or Mre11/Rad50 protein complex. J. Biol. Chem. 287, 4936–4945 (2012).
Google Scholar
Mimitou, E. P. & Symington, L. S. Ku prevents Exo1 and Sgs1-dependent resection of DNA ends in the absence of a functional MRX complex or Sae2. EMBO J. 29, 3358–3369 (2010).
Google Scholar
Deshpande, R. A. et al. DNA-dependent protein kinase promotes DNA end processing by MRN and CtIP. Sci. Adv. 6, eaay0922 (2020).
Google Scholar
Stewart, J. A. et al. Human CST promotes telomere duplex replication and general replication restart after fork stalling. EMBO J. 31, 3537–3549 (2012).
Google Scholar
Paniagua, I. et al. MAD2L2 promotes replication fork protection and recovery in a shieldin-independent and REV3L-dependent manner. Nat. Commun. 13, 5167 (2022).
Google Scholar
Mukherjee, C. et al. RIF1 promotes replication fork protection and efficient restart to maintain genome stability. Nat. Commun. 10, 3287 (2019).
Google Scholar
