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• W4280490934 abstract "Defects in DNA double-strand break repair are thought to render BRCA1 or BRCA2 (BRCA) mutant tumors selectively sensitive to PARP inhibitors (PARPis). Challenging this framework, BRCA and PARP1 share functions in DNA synthesis on the lagging strand. Thus, BRCA deficiency or “BRCAness” could reflect an inherent lagging strand problem that is vulnerable to drugs such as PARPi that also target the lagging strand, a combination that generates a toxic accumulation of replication gaps. Defects in DNA double-strand break repair are thought to render BRCA1 or BRCA2 (BRCA) mutant tumors selectively sensitive to PARP inhibitors (PARPis). Challenging this framework, BRCA and PARP1 share functions in DNA synthesis on the lagging strand. Thus, BRCA deficiency or “BRCAness” could reflect an inherent lagging strand problem that is vulnerable to drugs such as PARPi that also target the lagging strand, a combination that generates a toxic accumulation of replication gaps. Features that distinguish cancer from noncancer cells enable selective targeting. As compared with normal cells, tumors with mutations in the hereditary breast/ovarian cancer genes, BRCA1 or BRCA2 (BRCA), are selectively sensitive to poly(ADP-ribose) (PAR) polymerase (PARP) inhibitors (PARPis). Conventionally, PARPi sensitivity is attributed to BRCA-deficient cells being unable to prevent and repair DNA double-strand breaks (DSBs). This framework is based on the well-characterized role of the BRCA proteins in repairing DSBs by homologous recombination (HR). Moreover, BRCA proteins are expected to limit the formation of DSBs by promoting replication fork protection (FP). Accordingly, HR and FP defects or “BRCAness” guides the clinical use of PARPi. Here, we propose a distinct model in which PARPi toxicity stems from DNA replication-associated single-stranded DNA (ssDNA) gaps. In support of this model, the parameters of HR and FP deficiency fail to fully explain tumor response. Moreover, gaps, unlike DSBs, form in the immediate aftermath of PARPi treatment, are exacerbated in BRCA-deficient cells, and are suppressed upon PARPi resistance. We further propose that in addition to loss of BRCA and PARP1, other toxic interactions could derive from lagging strand synthesis problems, fork repriming, and/or other events that expand gap formation. To leverage these insights for precision medicine, rather than an HR-deficiency (HRD) score, a more precise and clinically significant measure will be a “gap” score. Ideally, the gap model of PARPi toxicity will broaden the range of treatable tumors and provide opportunities to develop robust drug combinations that maximize gaps and limit resistance. Genotoxic chemotherapy that exploits cancer cell defects in DNA repair has been the cornerstone of targeted therapy and applied clinically to tumors with mutations in the hereditary breast and ovarian cancer genes, BRCA1 or BRCA2 (BRCA). The promise of this strategy was revealed by the extreme sensitivity of BRCA mutant cancers upon inhibition of PARP (Bryant et al., 2005Bryant H.E. Schultz N. Thomas H.D. Parker K.M. Flower D. Lopez E. Kyle S. Meuth M. Curtin N.J. Helleday T. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase.Nature. 2005; 434: 913-917Crossref PubMed Scopus (3464) Google Scholar; Farmer et al., 2005Farmer H. McCabe N. Lord C.J. Tutt A.N. Johnson D.A. Richardson T.B. Santarosa M. Dillon K.J. Hickson I. Knights C. et al.Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy.Nature. 2005; 434: 917-921Crossref PubMed Scopus (4441) Google Scholar). PARP1, the major protein in PARP family, binds damaged DNA activating its poly(ADP-ribosyl)ation (PARylation) activity of itself and other proteins to facilitate DNA repair (Rose et al., 2020Rose M. Burgess J.T. O'Byrne K. Richard D.J. Bolderson E. PARP inhibitors: clinical relevance, mechanisms of action and tumor resistance.Front. Cell Dev. Biol. 2020; 8: 564601Crossref PubMed Scopus (96) Google Scholar). PARPis can “trap” PARP1 on damaged DNA and/or inactivate its PARylation activity, thereby generating a protein/DNA complex that can either block DNA replication and/or interfere with DNA damage repair (Murai et al., 2012Murai J. Huang S.Y. Das B.B. Renaud A. Zhang Y. Doroshow J.H. Ji J. Takeda S. Pommier Y. Trapping of PARP1 and PARP2 by clinical PARP inhibitors.Cancer Res. 2012; 72: 5588-5599Crossref PubMed Scopus (1221) Google Scholar; Pommier et al., 2016Pommier Y. O'Connor M.J. de Bono J. Laying a trap to kill cancer cells: PARP inhibitors and their mechanisms of action.Sci. Transl. Med. 2016; 8: 362ps317Crossref Scopus (371) Google Scholar; Ström et al., 2011Ström C.E. Johansson F. Uhlén M. Szigyarto C.A. Erixon K. Helleday T. Poly (ADP-ribose) polymerase (PARP) is not involved in base excision repair but PARP inhibition traps a single-strand intermediate.Nucleic Acids Res. 2011; 39: 3166-3175Crossref PubMed Scopus (216) Google Scholar). PARPi toxicity in BRCA-deficient cells is often referred to as a synthetic lethal interaction, a situation in which concurrent loss of two genes is cytotoxic, but their single loss is tolerated. Although cell killing due to the loss of both PARP1 and BRCA genes is consistent with a synthetic lethal interaction (Bryant et al., 2005Bryant H.E. Schultz N. Thomas H.D. Parker K.M. Flower D. Lopez E. Kyle S. Meuth M. Curtin N.J. Helleday T. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase.Nature. 2005; 434: 913-917Crossref PubMed Scopus (3464) Google Scholar; Farmer et al., 2005Farmer H. McCabe N. Lord C.J. Tutt A.N. Johnson D.A. Richardson T.B. Santarosa M. Dillon K.J. Hickson I. Knights C. et al.Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy.Nature. 2005; 434: 917-921Crossref PubMed Scopus (4441) Google Scholar), this designation falls short when toxicity instead derives from PARP trapping, given that this is not loss of a gene. Nevertheless, this so-called synthetic lethal interaction has propelled a revolution in cancer therapy (Lord and Ashworth, 2017Lord C.J. Ashworth A. PARP inhibitors: synthetic lethality in the clinic.Science. 2017; 355: 1152-1158Crossref PubMed Scopus (1169) Google Scholar). The sensitizing lesions following PARPi is generally thought to be DNA DSBs. Logically, DSBs necessitate BRCA function in DSB repair by HR. Moreover, given that PARPi is thought to trap PARP on DNA and/or block DNA replication, this further necessitates BRCA function in FP that limits the degradation and collapse of stalled replication forks into DSBs (Schlacher et al., 2011Schlacher K. Christ N. Siaud N. Egashira A. Wu H. Jasin M. Double-strand break repair-independent role for BRCA2 in blocking stalled replication fork degradation by MRE11.Cell. 2011; 145: 529-542Abstract Full Text Full Text PDF PubMed Scopus (759) Google Scholar; Schlacher et al., 2012Schlacher K. Wu H. Jasin M. A distinct replication fork protection pathway connects fanconi anemia tumor suppressors to RAD51-BRCA1/2.Cancer Cell. 2012; 22: 106-116Abstract Full Text Full Text PDF PubMed Scopus (578) Google Scholar). Thus, PARPi-induced DSBs and fork collapse are anticipated to be lethal in BRCA-deficient cells. To identify and predict tumors that will be sensitive to PARPi, much effort has been applied to scoring HRD tumors by mutational signatures, protein expression, and/or genome scaring events (van Wijk et al., 2022van Wijk L.M. Nilas A.B. Vrieling H. Vreeswijk M.P.G. RAD51 as a functional biomarker for homologous recombination deficiency in cancer: a promising addition to the HRD toolbox?.Expert Rev. Mol. Diagn. 2022; 22: 185-199Crossref PubMed Scopus (1) Google Scholar). The emergence of chemotherapy resistance in BRCA-deficient cancer cells also often correlated with restoration of HR and/or FP, furthering the model that a DSB is the sensitizing lesion (Cantor, 2021Cantor S.B. Revisiting the BRCA-pathway through the lens of replication gap suppression: Gaps determine therapy response in BRCA mutant cancer.DNA Repair. 2021; 107: 103209Crossref PubMed Scopus (5) Google Scholar). Here, we diverge and propose instead that the common vulnerability of cancer cells sensitive to PARPi is aberrant ssDNA gap formation occurring in the wake of DNA replication (also called daughter-strand gaps) (Wong et al., 2021Wong R.P. Petriukov K. Ulrich H.D. Daughter-strand gaps in DNA replication - substrates of lesion processing and initiators of distress signalling.DNA Repair. 2021; 105: 103163Crossref PubMed Scopus (6) Google Scholar). This premise is based on the finding that defects in gap suppression, as opposed to DSB repair of FP, more accurately align with therapy sensitivity and patient response in BRCA mutant cancer (Panzarino et al., 2021Panzarino N.J. Krais J.J. Cong K. Peng M. Mosqueda M. Nayak S.U. Bond S.M. Calvo J.A. Doshi M.B. Bere M. et al.Replication gaps underlie BRCA deficiency and therapy response.Cancer Res. 2021; 81: 1388-1397Crossref PubMed Scopus (37) Google Scholar). Replication gaps as opposed to DSBs also align more with PARPi response (Cong et al., 2021Cong K. Peng M. Kousholt A.N. Lee W.T.C. Lee S. Nayak S. Krais J. VanderVere-Carozza P.S. Pawelczak K.S. Calvo J. et al.Replication gaps are a key determinant of PARP inhibitor synthetic lethality with BRCA deficiency.Mol. Cell. 2021; 81: 3128-3144.e7Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar; Paes Dias et al., 2021Paes Dias M. Tripathi V. van der Heijden I. Cong K. Manolika E.M. Bhin J. Gogola E. Galanos P. Annunziato S. Lieftink C. et al.Loss of nuclear DNA ligase III reverts PARP inhibitor resistance in BRCA1/53BP1 double-deficient cells by exposing ssDNA gaps.Mol. Cell. 2021; 81: 4692-4708.e9Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar). Accordingly, limiting replication gaps is a function enacted by the BRCA-RAD51 pathway that is distinct from its roles in HR and FP (Hashimoto et al., 2010Hashimoto Y. Ray Chaudhuri A. Lopes M. Costanzo V. Rad51 protects nascent DNA from Mre11-dependent degradation and promotes continuous DNA synthesis.Nat. Struct. Mol. Biol. 2010; 17: 1305-1311Crossref PubMed Scopus (337) Google Scholar; Kang et al., 2021Kang Z. Fu P. Alcivar A.L. Fu H. Redon C. Foo T.K. Zuo Y. Ye C. Baxley R. Madireddy A. et al.BRCA2 associates with MCM10 to suppress PRIMPOL-mediated repriming and single-stranded gap formation after DNA damage.Nat. Commun. 2021; 12: 5966PubMed Google Scholar; Kolinjivadi et al., 2017Kolinjivadi A.M. Sannino V. De Antoni A. Zadorozhny K. Kilkenny M. Técher H. Baldi G. Shen R. Ciccia A. Pellegrini L. et al.Smarcal1-mediated fork reversal triggers Mre11-dependent degradation of nascent DNA in the absence of Brca2 and stable Rad51 nucleofilaments.Mol. Cell. 2017; 67: 867-881.e7Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar; Panzarino et al., 2021Panzarino N.J. Krais J.J. Cong K. Peng M. Mosqueda M. Nayak S.U. Bond S.M. Calvo J.A. Doshi M.B. Bere M. et al.Replication gaps underlie BRCA deficiency and therapy response.Cancer Res. 2021; 81: 1388-1397Crossref PubMed Scopus (37) Google Scholar; Simoneau et al., 2021Simoneau A. Xiong R. Zou L. The trans cell cycle effects of PARP inhibitors underlie their selectivity toward BRCA1/2-deficient cells.Genes Dev. 2021; 35: 1271-1289Crossref PubMed Google Scholar; Taglialatela et al., 2021Taglialatela A. Leuzzi G. Sannino V. Cuella-Martin R. Huang J.W. Wu-Baer F. Baer R. Costanzo V. Ciccia A. REV1-Polzeta maintains the viability of homologous recombination-deficient cancer cells through mutagenic repair of PRIMPOL-dependent ssDNA gaps.Mol. Cell. 2021; 81: 4008-4025.e7Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar; Tirman et al., 2021Tirman S. Quinet A. Wood M. Meroni A. Cybulla E. Jackson J. Pegoraro S. Simoneau A. Zou L. Vindigni A. Temporally distinct post-replicative repair mechanisms fill PRIMPOL-dependent ssDNA gaps in human cells.Mol. Cell. 2021; 81: 4026-4040.e8Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar; Zellweger et al., 2015Zellweger R. Dalcher D. Mutreja K. Berti M. Schmid J.A. Herrador R. Vindigni A. Lopes M. Rad51-mediated replication fork reversal is a global response to genotoxic treatments in human cells.J. Cell Biol. 2015; 208: 563-579Crossref PubMed Scopus (366) Google Scholar). The source of gaps has been linked to defects in both lagging strand synthesis and repriming reactions occurring on the leading strand (Cantor, 2021Cantor S.B. Revisiting the BRCA-pathway through the lens of replication gap suppression: Gaps determine therapy response in BRCA mutant cancer.DNA Repair. 2021; 107: 103209Crossref PubMed Scopus (5) Google Scholar). We further predict that tumors with mutations in BRCA and other genes that share the phenotype of BRCAness are vulnerable to gap inducing genotoxic therapies such as PARPi. Finally, we expect that gaps are relevant to a range of synthetic lethal or toxic interactions. The analysis of DNA replication-associated ssDNA gaps in the immediate aftermath of PARPi treatment revealed fundamental differences between sensitive and resistant lines. In resistant BRCA-proficient control cells, gaps were restricted, whereas in sensitive BRCA-deficient cells, gaps were enhanced (Cong et al., 2021Cong K. Peng M. Kousholt A.N. Lee W.T.C. Lee S. Nayak S. Krais J. VanderVere-Carozza P.S. Pawelczak K.S. Calvo J. et al.Replication gaps are a key determinant of PARP inhibitor synthetic lethality with BRCA deficiency.Mol. Cell. 2021; 81: 3128-3144.e7Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar). Moreover, gaps were suppressed in a series of genetic and acquired models in which PARPi resistance was thought to derive from restored HR and/or FP. Gaps were also suppressed in cancer cell lines and patient-derived tumors with de novo PARPi resistance in which the mechanism was undefined. More strikingly, PARPi resistance was observed in cells deficient in HR and FP. In particular, cells null for the BRCA1-associated helicase, Fanconi anemia complementation group J (FANCJ), displayed PARPi insensitivity despite defects in HR and FP. Another important observation is that PARPi-induced gaps were avoided in the FANCJ null cells. By comparison, gaps were elevated in Fanconi anemia (FA) patient cells that maintain a single-allele mutation in the recombination gene RAD51. The FA cells were PARPi sensitive despite proficiency in HR and the additional restoration FP. Thus, PARPi response can be uncoupled from HR and FP (Cong et al., 2021Cong K. Peng M. Kousholt A.N. Lee W.T.C. Lee S. Nayak S. Krais J. VanderVere-Carozza P.S. Pawelczak K.S. Calvo J. et al.Replication gaps are a key determinant of PARP inhibitor synthetic lethality with BRCA deficiency.Mol. Cell. 2021; 81: 3128-3144.e7Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar), a finding implicating gaps alone could be fundamental to therapy response. Gaps were also rapidly induced (minutes to hours), whereas DSBs formed later (hours to days). This latency could reflect that unrepaired ssDNA breaks or PARP-trapped complexes eventually block DNA replication to induce DSBs. Inconsistent with a fork arrest model, however, PARPi-treated cells display replication tracts that appear longer (Maya-Mendoza et al., 2018Maya-Mendoza A. Moudry P. Merchut-Maya J.M. Lee M. Strauss R. Bartek J. High speed of fork progression induces DNA replication stress and genomic instability.Nature. 2018; 559: 279-284Crossref PubMed Scopus (217) Google Scholar). Notably, these “lengthened” tracts are sensitive to S1 nuclease cutting, implicating discontinuous DNA replication (Cong et al., 2021Cong K. Peng M. Kousholt A.N. Lee W.T.C. Lee S. Nayak S. Krais J. VanderVere-Carozza P.S. Pawelczak K.S. Calvo J. et al.Replication gaps are a key determinant of PARP inhibitor synthetic lethality with BRCA deficiency.Mol. Cell. 2021; 81: 3128-3144.e7Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar). Although these gaps could seed DSBs in a subsequent S phase (Simoneau et al., 2021Simoneau A. Xiong R. Zou L. The trans cell cycle effects of PARP inhibitors underlie their selectivity toward BRCA1/2-deficient cells.Genes Dev. 2021; 35: 1271-1289Crossref PubMed Google Scholar), there are other potential sources for DSB formation. PARPi also induces apoptosis, a cell death process involving enzymes that cut DNA. Inhibition of apoptosis reduced DSBs, indicating that breaks derive in large part from apoptosis (Cong et al., 2021Cong K. Peng M. Kousholt A.N. Lee W.T.C. Lee S. Nayak S. Krais J. VanderVere-Carozza P.S. Pawelczak K.S. Calvo J. et al.Replication gaps are a key determinant of PARP inhibitor synthetic lethality with BRCA deficiency.Mol. Cell. 2021; 81: 3128-3144.e7Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar). Gaps are also not necessarily precursors to stalled/collapsed forks. Gaps appear as separate entities and degrade/extend under distinct conditions (Somyajit et al., 2021Somyajit K. Spies J. Coscia F. Kirik U. Rask M.B. Lee J.H. Neelsen K.J. Mund A. Jensen L.J. Paull T.T. et al.Homology-directed repair protects the replicating genome from metabolic assaults.Dev. Cell. 2021; 56: 461-477.e7Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar; Wong et al., 2020Wong R.P. García-Rodríguez N. Zilio N. Hanulová M. Ulrich H.D. Processing of DNA polymerase-blocking lesions during genome replication is spatially and temporally segregated from replication forks.Mol. Cell. 2020; 77: 3-16.e4Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar). Taken as a whole, the relevance of DSBs remains unclear, whereas gaps are consistently linked with PARPi response, inspiring a revised model of therapy response (Figure 1). When canonical Okazaki fragment processing (OFP) is incomplete and ssDNA gaps remain in the lagging strand, PARP1 is activated. PARP1’s auto-PARylation recruits X-ray repair cross-complementing protein 1 (XRCC1), a scaffold protein that interacts with DNA ligase 3 (LIG3) and DNA polymerase β (POLβ) to process and fill gaps in a mechanism termed backup OFP that is fundamental to the completion of lagging strand synthesis in unperturbed cells (Hanzlikova et al., 2018Hanzlikova H. Kalasova I. Demin A.A. Pennicott L.E. Cihlarova Z. Caldecott K.W. The importance of poly(ADP-ribose) polymerase as a sensor of unligated Okazaki fragments during DNA replication.Mol. Cell. 2018; 71: 319-331.e3Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar). Unexpectantly, this PARP1-backup OFP mechanism requires the BRCA-RAD51 pathway. In BRCA1-deficient cells, lagging strand-dependent PARP1 activation is abnormally elevated. However, the hyperactivated PARP1 fails to effectively recruit XRCC1 and LIG3 (Cong et al., 2021Cong K. Peng M. Kousholt A.N. Lee W.T.C. Lee S. Nayak S. Krais J. VanderVere-Carozza P.S. Pawelczak K.S. Calvo J. et al.Replication gaps are a key determinant of PARP inhibitor synthetic lethality with BRCA deficiency.Mol. Cell. 2021; 81: 3128-3144.e7Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar). Consistent with a defect in the backup pathway, BRCA1-deficient cells demonstrate a greater reliance on canonical lagging strand synthesis. They have a heightened sensitivity to loss of the canonical flap endonuclease 1 (FEN1) that generates ligatable nicks (Cong et al., 2021Cong K. Peng M. Kousholt A.N. Lee W.T.C. Lee S. Nayak S. Krais J. VanderVere-Carozza P.S. Pawelczak K.S. Calvo J. et al.Replication gaps are a key determinant of PARP inhibitor synthetic lethality with BRCA deficiency.Mol. Cell. 2021; 81: 3128-3144.e7Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar; Guo et al., 2020Guo E. Ishii Y. Mueller J. Srivatsan A. Gahman T. Putnam C.D. Wang J.Y.J. Kolodner R.D. FEN1 endonuclease as a therapeutic target for human cancers with defects in homologous recombination.Proc. Natl. Acad. Sci. USA. 2020; 117: 19415-19424Crossref PubMed Scopus (29) Google Scholar; Mengwasser et al., 2019Mengwasser K.E. Adeyemi R.O. Leng Y. Choi M.Y. Clairmont C. D'Andrea A.D. Elledge S.J. Genetic screens reveal FEN1 and APEX2 as BRCA2 synthetic lethal targets.Mol. Cell. 2019; 73: 885-899.e6Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar; Ward et al., 2017Ward T.A. McHugh P.J. Durant S.T. Small molecule inhibitors uncover synthetic genetic interactions of human flap endonuclease 1 (FEN1) with DNA damage response genes.PLoS One. 2017; 12: e0179278Crossref PubMed Scopus (25) Google Scholar). Given that PARPi also hinders the maturation of nascent DNA strands during DNA replication (Vaitsiankova et al., 2022Vaitsiankova A. Burdova K. Sobol M. Gautam A. Benada O. Hanzlikova H. Caldecott K.W. PARP inhibition impedes the maturation of nascent DNA strands during DNA replication.Nat. Struct. Mol. Biol. 2022; 29: 329-338Crossref PubMed Scopus (4) Google Scholar), these findings implicate that lagging strand synthesis is a vulnerability in BRCA-deficient cells underlying the cytotoxicity of PARPi. Intriguingly, backup OFP improves substantially in BRCA-RAD51-deficient cells that gain PARPi resistance. Along with gap suppression, the aberrant S-phase PARylation is significantly reduced (Cong et al., 2021Cong K. Peng M. Kousholt A.N. Lee W.T.C. Lee S. Nayak S. Krais J. VanderVere-Carozza P.S. Pawelczak K.S. Calvo J. et al.Replication gaps are a key determinant of PARP inhibitor synthetic lethality with BRCA deficiency.Mol. Cell. 2021; 81: 3128-3144.e7Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar). Even in the well-characterized genetic model in which BRCA1-deficient cells gain PARPi resistance by loss of the DNA repair protein, p53 binding protein 1 (53BP1), gaps, and PAR are dramatically suppressed. Consistent with this rescue occurring via restored OFP, the chromatin association of XRCC1 and LIG3 are also re-established at levels above those in control cells. Moreover, sensitivity to FEN1 loss is mitigated indicating reduced reliance on canonical OFP (Cong et al., 2021Cong K. Peng M. Kousholt A.N. Lee W.T.C. Lee S. Nayak S. Krais J. VanderVere-Carozza P.S. Pawelczak K.S. Calvo J. et al.Replication gaps are a key determinant of PARP inhibitor synthetic lethality with BRCA deficiency.Mol. Cell. 2021; 81: 3128-3144.e7Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar). However, a new vulnerability arises. In this dual BRCA1 and 53BP1 deficiency background, the top target from a genetic screen to revert the PARPi resistance is LIG3 (Paes Dias et al., 2021Paes Dias M. Tripathi V. van der Heijden I. Cong K. Manolika E.M. Bhin J. Gogola E. Galanos P. Annunziato S. Lieftink C. et al.Loss of nuclear DNA ligase III reverts PARP inhibitor resistance in BRCA1/53BP1 double-deficient cells by exposing ssDNA gaps.Mol. Cell. 2021; 81: 4692-4708.e9Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar). Remarkably, this screen did not predominantly identify HR genes which one would expect if loss of 53BP1 conferred PARPi resistance via HR. Other LIG3 functions (i.e., base excision repair) cannot be ruled out. However, the relevance of backup OFP is supported. BRCA1 and 53BP1 dual-deficient cells have enhanced PAR upon depletion of LIG3 as compared with depletion of FEN1 or DNA ligase 1 (LIG1), the major enzyme joining Okazaki fragments, findings that are reversed in control cells (Cong et al., 2021Cong K. Peng M. Kousholt A.N. Lee W.T.C. Lee S. Nayak S. Krais J. VanderVere-Carozza P.S. Pawelczak K.S. Calvo J. et al.Replication gaps are a key determinant of PARP inhibitor synthetic lethality with BRCA deficiency.Mol. Cell. 2021; 81: 3128-3144.e7Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar). Thus, BRCA1 and 53BP1 dual-deficient cells appear to require LIG3 not only for viability but also for normal S-phase PAR levels. These new insights implicate that an acquired vulnerability in cells dually deficient in BRCA1 and 53BP1 includes backup OFP that also could be the target of drugs resensitizing to PARPi. A source of gaps in BRCA-deficient cells is also linked to repriming reactions on the leading strand by the DNA primase/polymerase (PRIMPOL) (Kang et al., 2021Kang Z. Fu P. Alcivar A.L. Fu H. Redon C. Foo T.K. Zuo Y. Ye C. Baxley R. Madireddy A. et al.BRCA2 associates with MCM10 to suppress PRIMPOL-mediated repriming and single-stranded gap formation after DNA damage.Nat. Commun. 2021; 12: 5966PubMed Google Scholar; Quinet et al., 2020Quinet A. Tirman S. Jackson J. Šviković S. Lemaçon D. Carvajal-Maldonado D. González-Acosta D. Vessoni A.T. Cybulla E. Wood M. et al.PRIMPOL-mediated adaptive response suppresses replication fork reversal in BRCA-deficient cells.Mol. Cell. 2020; 77: 461-474.e9Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar; Simoneau et al., 2021Simoneau A. Xiong R. Zou L. The trans cell cycle effects of PARP inhibitors underlie their selectivity toward BRCA1/2-deficient cells.Genes Dev. 2021; 35: 1271-1289Crossref PubMed Google Scholar; Taglialatela et al., 2021Taglialatela A. Leuzzi G. Sannino V. Cuella-Martin R. Huang J.W. Wu-Baer F. Baer R. Costanzo V. Ciccia A. REV1-Polzeta maintains the viability of homologous recombination-deficient cancer cells through mutagenic repair of PRIMPOL-dependent ssDNA gaps.Mol. Cell. 2021; 81: 4008-4025.e7Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar; Tirman et al., 2021Tirman S. Quinet A. Wood M. Meroni A. Cybulla E. Jackson J. Pegoraro S. Simoneau A. Zou L. Vindigni A. Temporally distinct post-replicative repair mechanisms fill PRIMPOL-dependent ssDNA gaps in human cells.Mol. Cell. 2021; 81: 4026-4040.e8Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar; Figure 2A). PRIMPOL enables the repriming of replication past obstacles when fork reversal is compromised. For example, repriming is linked to PRIMPOL during PARPi treatment. Without PARylated PARP1, fork reversal is counteracted by the RecQ like helicase 1 (RECQ1) (Berti et al., 2013Berti M. Ray Chaudhuri A. Thangavel S. Gomathinayagam S. Kenig S. Vujanovic M. Odreman F. Glatter T. Graziano S. Mendoza-Maldonado R. et al.Human RECQ1 promotes restart of replication forks reversed by DNA topoisomerase I inhibition.Nat. Struct. Mol. Biol. 2013; 20: 347-354Crossref PubMed Scopus (267) Google Scholar; Zellweger et al., 2015Zellweger R. Dalcher D. Mutreja K. Berti M. Schmid J.A. Herrador R. Vindigni A. Lopes M. Rad51-mediated replication fork reversal is a global response to genotoxic treatments in human cells.J. Cell Biol. 2015; 208: 563-579Crossref PubMed Scopus (366) Google Scholar). Similarly, loss of the fork remodeler, helicase-like transcription factor (HLTF), reduces fork reversal and gaps form in a manner dependent on PRIMPOL as well as FANCJ (Bai et al., 2020Bai G. Kermi C. Stoy H. Schiltz C.J. Bacal J. Zaino A.M. Hadden M.K. Eichman B.F. Lopes M. Cimprich K.A. HLTF promotes fork reversal, limiting replication stress resistance and preventing multiple mechanisms of unrestrained DNA synthesis.Mol. Cell. 2020; 78: 1237-1251.e7Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar; Peng et al., 2018Peng M. Cong K. Panzarino N.J. Nayak S. Calvo J. Deng B. Zhu L.J. Morocz M. Hegedus L. Haracska L. et al.Opposing roles of FANCJ and HLTF protect forks and restrain replication during stress.Cell Rep. 2018; 24: 3251-3261Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar). Based on these findings, it appears that the lack of fork reversal propels repriming of the forward fork. Counterintuitively, a process known as fork traverse that enables replication past cross-links (Huang et al., 2013Huang J. Liu S. Bellani M.A. Thazhathveetil A.K. Ling C. de Winter J.P. Wang Y. Wang W. Seidman M.M. The DNA translocase FANCM/MHF promotes replication traverse of DNA interstrand crosslinks.Mol. Cell. 2013; 52: 434-446Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar) not only engages PRIMPOL (González-Acosta et al., 2021González-Acosta D. Blanco-Romero E. Ubieto-Capella P. Mutreja K. Míguez S. Llanos S. García F. Muñoz J. Blanco L. Lopes M. et al.PrimPol-mediated repriming facilitates replication traverse of DNA interstrand crosslinks.EMBO J. 2021; 40: e106355Crossref PubMed Scopus (11) Google Scholar) but also requires fork reversal (Mutreja et al., 2018Mutreja K. Krietsch J. Hess J. Ursich S. Berti M. Roessler F.K. Zellweger R. Patra M. Gasser G. Lopes M. ATR-mediated global fork slowing and reversal assist fork traverse and prevent chromosomal breakage at DNA interstrand cross-links.Cell Rep. 2018; 24: 2629-2642.e5Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar). Perhaps to engage repriming, fork reversal is required even if transient as might occur with PARPi or loss of HLTF. Another interesting possibility is that defects in OFP are coupled to repriming reactions. OFP defects could confer topological stress that triggers fork reversal but in turn limits end processing required for restart, necessitating fork repriming for replication to continue (Figure 2B). Indeed, defects in OFP through loss of FEN1 or ribonuclease H2 (RNase H2) in a yeast model impairs nascent strand resection at reversed forks (Audoynaud et al., 2022Audoynaud C. Ait Saada A. Fernández Varela P. Gesnik A. Boucherit V. Ropars V. Fréon K. Charbonnier J.B. Lambert S. RNA:DNA hybrids from Okazaki fragment are cis-regulators of Ku function in safeguarding replication fork integrity.2022https://doi.org/10.2139/ssrn.4017909https://ssrn.com/abstract=4017909Crossref Google Scholar). Conceivably, a reversed fork could be rescued by repriming on the leading strand via PRIMPOL. A rapid interchange between OFP defects, reversal, and repriming in a hyper-dynamic fork could reveal only gaps in the wake of DNA replication. In this context, it is also interesting that gap" @default.
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• W4280490934 title "Exploiting replication gaps for cancer therapy" @default.
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• W4280490934 doi "https://doi.org/10.1016/j.molcel.2022.04.023" @default.
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