Preserving replication fork integrity and competence via the homologous recombination pathway

Saada, Anissia Ait; Lambert, Sarah; Carr, Antony

doi:10.1016/j.dnarep.2018.08.017

Cited by 144 publications

(129 citation statements)

References 124 publications

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“…Replication forks are prone to breakage if they encounter an SSB, which is why homologous recombination is a critical pathway for repairing replication forks to prevent fork collapse (Ait Saada et al 2018). PARP1 contributes to the homologous recombination pathway of DSB repair by promoting rapid recruitment of MRE11, EXO1, BRCA1, and BRCA2 to DNA damage sites ( Fig.…”

Section: Functions Of Parp1 and Parg In Dna Repair And Replication Fomentioning

confidence: 99%

PARP and PARG inhibitors in cancer treatment

2020

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Oxidative and replication stress underlie genomic instability of cancer cells. Amplifying genomic instability through radiotherapy and chemotherapy has been a powerful but nonselective means of killing cancer cells. Precision medicine has revolutionized cancer therapy by putting forth the concept of selective targeting of cancer cells. Poly(ADP-ribose) polymerase (PARP) inhibitors represent a successful example of precision medicine as the first drugs targeting DNA damage response to have entered the clinic. PARP inhibitors act through synthetic lethality with mutations in DNA repair genes and were approved for the treatment of BRCA mutated ovarian and breast cancer. PARP inhibitors destabilize replication forks through PARP DNA entrapment and induce cell death through replication stress-induced mitotic catastrophe. Inhibitors of poly(ADP-ribose) glycohydrolase (PARG) exploit and exacerbate replication deficiencies of cancer cells and may complement PARP inhibitors in targeting a broad range of cancer types with different sources of genomic instability. Here I provide an overview of the molecular mechanisms and cellular consequences of PARP and PARG inhibition. I highlight clinical performance of four PARP inhibitors used in cancer therapy (olaparib, rucaparib, niraparib, and talazoparib) and discuss the predictive biomarkers of inhibitor sensitivity, mechanisms of resistance as well as the means of overcoming them through combination therapy.

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Section: Functions Of Parp1 and Parg In Dna Repair And Replication Fomentioning

confidence: 99%

PARP and PARG inhibitors in cancer treatment

2020

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“…6G,H), the function of Rad52 in the absence of checkpoint inhibition of origin firing is not clear. We cannot rule out that DSBs do form at some point due to excess origin firing, but we note that HR proteins resolve replication fork intermediates in the absence of DSBs (Kolinjivadi et al 2017;Ait Saada et al 2018). Indeed, a significant consequence of topological defects is fork reversal, whereby positive supercoiling ahead of the replisome drives nascent DNA at the fork to regress and anneal to generate a four-way junction (Postow et al 2001;Neelsen and Lopes 2015).…”

Section: Role Of Checkpoint Inhibition Of Origin Firingmentioning

confidence: 91%

Checkpoint inhibition of origin firing prevents DNA topological stress

et al. 2019

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A universal feature of DNA damage and replication stress in eukaryotes is the activation of a checkpoint-kinase response. In S-phase, the checkpoint inhibits replication initiation, yet the function of this global block to origin firing remains unknown. To establish the physiological roles of this arm of the checkpoint, we analyzed separation of function mutants in the budding yeast Saccharomyces cerevisiae that allow global origin firing upon replication stress, despite an otherwise normal checkpoint response. Using genetic screens, we show that lack of the checkpoint-block to origin firing results in a dependence on pathways required for the resolution of topological problems. Failure to inhibit replication initiation indeed causes increased DNA catenation, resulting in DNA damage and chromosome loss. We further show that such topological stress is not only a consequence of a failed checkpoint response but also occurs in an unperturbed S-phase when too many origins fire simultaneously. Together we reveal that the role of limiting the number of replication initiation events is to prevent DNA topological problems, which may be relevant for the treatment of cancer with both topoisomerase and checkpoint inhibitors.

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“…CPT-trapped Top1cc or MMS-mediated DNA methylation stalls DNA replication in S phase, which has to be resolved to allow the completion of DNA replication. Mechanisms for the restart of DNA replication may involve the generation of altered fork structures (as fork restart intermediates) harboring ssDNA gaps that can trigger DDC (98). We imagine that these distorted fork structures are different from resected (simple) DSBs induced by phleomycin or IR in influencing γH2A interaction with Rad9 and/or Slx4/Rtt107.…”

Section: Dna Damage-specific Impacts Of γH2a On Ddcmentioning

confidence: 99%

DNA damage-specific effects of Tel1/ATM and γH2A/γH2AX on checkpoint signaling inSaccharomyces cerevisiae

Siler

Guo

Liu

et al. 2019

Preprint

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DNA lesions trigger the activation of DNA damage checkpoints (DDCs) that stop cell cycle progression and promote DNA damage repair. Saccharomyces cerevisiae Tel1 is a homolog of mammalian ATM kinase that plays an auxiliary role in DDC signaling. γH2A, equivalent to γH2AX in mammals, is an early chromatin mark induced by DNA damage that is recognized by a group of DDC and DNA repair factors. We find that both Tel1 and γH2A negatively impact G2/M checkpoint in response to DNA topoisomerase I poison camptothecin independently of each other. γH2A also negatively regulates DDC induced by DNA alkylating agent methyl methanesulfonate. These results, together with prior findings demonstrating positive or no roles of Tel1 and γH2A in DDC in response to other DNA damaging agents such as phleomycin and ionizing radiation, suggest that Tel1 and γH2A have DNA damage-specific effects on DDC. We present data indicating that Tel1 acts in the same pathway as Mre11-Rad50-Xrs2 complex to suppress CPT induced DDC possibly by repairing topoisomerase I-DNA crosslink. On the other hand, we find evidence consistent with the notion that γH2A regulates DDC by mediating the competitive recruitment of DDC mediator Rad9 and DNA repair factor Rtt107 to sites of DNA damage. We propose that γH2A serves to create a dynamic balance between DDC and DNA repair that is influenced by the nature of DNA damage. signaling requires both the apical ATM and ATR kinases (2), whereas in the yeast Saccharomyces cerevisiae, the ATR homolog Mec1 plays an essential role in DDC, but the ATM homolog Tel1 only plays an auxiliary role that is usually masked by the prevailing activity of Mec1 (3-6).The activation of DDC is intimately coupled with the generation of single stranded DNA (ssDNA) due to DSB end resection or replicative stress (7,8). The 3' ssDNA resulted from DSB end resection also allows DSB repair by homology-based repair mechanisms. DSBs are recognized by Mre11-Rad50-Xrs2 (MRX) complex together with Sae2 (9) (Fig. 1B). MRX recruits Tel1 to DSBs and activates its kinase activity (9-11). Tel1 then supports MRX function in a positive feedback loop by stabilizing MRX association with DSBs, which is important for MRX mediated DSB repair (9,12). In addition, Tel1 phosphorylates Sae2, stimulating its activity (13,14) ( Fig. 1B). Tel1 also phosphorylates histone H2A at its carboxyl-terminal serine 129 (equivalent to serine 139 of histone variant H2AX in mammals) creating H2A-S129-P, or γH2A (equivalent to mammalian γH2AX) containing nucleosomes (15) ( Fig. 1B). Note H2A-S129 in chromatin surrounding DSB is also subject to phosphorylation by Mec1 later during DDC signaling (7,16-18) (Fig. 1D).The Mre11 subunit of MRX has both ssDNA endonuclease activity and 3'à5' dsDNA exonuclease activity (19)(20)(21)(22). Sae2 activates the ssDNA endonuclease activity of Mre11 that is responsible for the incision of the 5' strand of DSB (23,24) ( Fig. 1B, blue arrow). MRX also helps to recruit the 5'à3' exonuclease Exo1 and Dna2 endonuclease complexed with Sgs1 helicase, Top3...

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Preserving replication fork integrity and competence via the homologous recombination pathway

Cited by 144 publications

References 124 publications

PARP and PARG inhibitors in cancer treatment

PARP and PARG inhibitors in cancer treatment

Checkpoint inhibition of origin firing prevents DNA topological stress

DNA damage-specific effects of Tel1/ATM and γH2A/γH2AX on checkpoint signaling inSaccharomyces cerevisiae

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