Control of homologous recombination by the HROB–MCM8–MCM9 pathway

Hustedt, Nicole; Saito, Yuichiro; Zimmermann, Michal; Álvarez-Quilón, Alejandro; Setiaputra, Dheva; Adam, Salomé; McEwan, Andrea; Yuan, Jing; Olivieri, Michele; Zhao, Yichao; Kanemaki, Masato T.; Jurisicova, Andrea; Durocher, Daniel

doi:10.1101/gad.329508.119

Cited by 64 publications

(103 citation statements)

References 52 publications

(76 reference statements)

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“…Collectively, these findings highlight the importance of MCM8IP in promoting DNA damage-associated DNA synthesis at replication and recombination intermediates. These observations are in line with the findings of a recent study on C17orf53 (renamed HROB by the authors) that was published during the revisions of our manuscript 52 .…”

Section: Discussionsupporting

confidence: 93%

“…5d, e). Regardless of whether MCM8IP loading occurs as a consequence of RPA interaction and/or direct ssDNA binding, once on damaged chromatin MCM8IP may facilitate the localization of MCM8-9 at DNA repair sites, as previously suggested 52 , in line with our findings that MCM8IP increases the affinity of MCM8-9 for ssDNA-containing DNA structures (Fig. 4a, b).…”

Section: Discussionsupporting

confidence: 91%

“…It has been proposed that RPA-coated D-loops may serve to localize the MCM8IP-MCM8-9 complex to sites of DNA synthesis during HR 52 . In agreement with those findings, we demonstrate that interaction with RPA1 is indeed required for optimal loading of MCM8IP onto damaged chromatin (Fig.…”

Section: Discussionmentioning

confidence: 99%

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MCM8IP activates the MCM8-9 helicase to promote DNA synthesis and homologous recombination upon DNA damage

et al. 2020

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Homologous recombination (HR) mediates the error-free repair of DNA double-strand breaks to maintain genomic stability. Here we characterize C17orf53/MCM8IP, an OB-fold containing protein that binds ssDNA, as a DNA repair factor involved in HR. MCM8IPdeficient cells exhibit HR defects, especially in long-tract gene conversion, occurring downstream of RAD51 loading, consistent with a role for MCM8IP in HR-dependent DNA synthesis. Moreover, loss of MCM8IP confers cellular sensitivity to crosslinking agents and PARP inhibition. Importantly, we report that MCM8IP directly associates with MCM8-9, a helicase complex mutated in primary ovarian insufficiency, and RPA1. We additionally show that the interactions of MCM8IP with MCM8-9 and RPA facilitate HR and promote replication fork progression and cellular viability in response to treatment with crosslinking agents. Mechanistically, MCM8IP stimulates the helicase activity of MCM8-9. Collectively, our work identifies MCM8IP as a key regulator of MCM8-9-dependent DNA synthesis during DNA recombination and replication.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 91%

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MCM8IP activates the MCM8-9 helicase to promote DNA synthesis and homologous recombination upon DNA damage

et al. 2020

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“…A recently discovered ICL factor is HROB. 5 Other previously uncharacterized genes in this cluster are CCRR1 and TXNDC17. CCAR1 is associated with DNA damage-induced apoptosis, while inactivation of TXNDC17 sensitized cells to methylating genotoxins and cisplatin, but not KBrO 3 .…”

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confidence: 94%

A genome-wide screening for DNA repair genes: much more players than hitherto known

Kaina

2020

Sig Transduct Target Ther

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“…In this issue of Genes & Development, Hustedt et al (2019) identify a new factor-HROB (HR OB-fold)-that functions closely with MCM8-9 in HR. Rationalizing that HR defects should cause sensitivity to inhibitors of ATR kinase and PARP, the investigators mined published CRISPR screens to identify new genes whose deletion sensitizes to both drug classes.…”

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confidence: 99%

Ways to unwind with HROB, a new player in homologous recombination

Saredi

Rouse

2019

Genes Dev.

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Homologous recombination (HR) is an important route for repairing DNA double-strand breaks (DSBs). The early stages of HR are well understood, but later stages remain mysterious. In this issue of Genes & Development, Hustedt and colleagues (pp. 1397-1415) reveal HROB as a new player in HR required for recruitment of the MCM8-9 complex, which is paralogous to the MCM2-7 replicative helicase. HROB functions closely with MCM8-9 to promote postsynaptic DNA repair synthesis. This study sheds valuable light on late events in HR and suggests that HROB may load MCM8-9 onto HR intermediates to facilitate the DNA unwinding required for DNA repair synthesis.Homologous recombination (HR) is a major route for repairing DNA double-strand breaks (DSBs) (Prakash et al. 2015). HR starts with resection of broken DNA ends, involving nucleases and helicases. The resulting overhangs, coated by RAD51 to yield a nucleoprotein filament, invade the intact sister chromatid, searching for a homologous sequence. The pairing of RAD51-coated single-stranded DNA (ssDNA) with the donor strand (termed synapsis) results in the displacement of the strand complementary to the donor (forming a structure called a "D loop") and the establishment of a RAD51-bound heteroduplex species that primes DNA repair synthesis (Fig. 1). The postsynaptic stages of HR are poorly understood, but a number of proteins are involved at this stage specifcially. For example, the MCM8 and MCM9 proteins, which are related to the subunits of the hexameric MCM2-7 replicative helicase, have been implicated in postsynaptic DNA synthesis. In contrast to MCM2-7, the MCM8-9 complex is dispensable for bulk DNA replication (Griffin and Trakselis 2019). The residual DNA synthesis that is maintained in MCM2-depleted cells requires MCM8-9, but this reflects DNA repair synthesis occurring during HR-mediated repair of the high level of DSBs that occur upon MCM2 depletion (Natsume et al. 2017). Importantly, MCM8-9 was shown to act downstream from RAD51 in the HR-mediated repair of DSBs induced by nuclease overexpression, in meiotic HR, and during the HR stage of DNA interstrand cross-link (ICL) repair (Lutzmann et al. 2012;Nishimura et al. 2012;Natsume et al. 2017). The dominant mode of ICL repair is initiated by collision of replisomes with ICLs, resulting in programmed formation of DSBs that are repaired by HR. Crucially, point mutations in MCM8-9 predicted to abolish helicase activity suppress ICL repair, suggesting that helicase activity is important for HR (Nishimura et al. 2012). One explanation is that MCM8-9 might facilitate postsynaptic DNA repair synthesis by unwinding D loops and enabling extension of the invading RAD51-coated DNA end (Fig. 1).In this issue of Genes & Development, Hustedt et al. (2019) identify a new factor-HROB (HR OB-fold)-that functions closely with MCM8-9 in HR. Rationalizing that HR defects should cause sensitivity to inhibitors of ATR kinase and PARP, the investigators mined published CRISPR screens to identify new genes whose deletion sensitizes to both...

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Control of homologous recombination by the HROB–MCM8–MCM9 pathway

Cited by 64 publications

References 52 publications

MCM8IP activates the MCM8-9 helicase to promote DNA synthesis and homologous recombination upon DNA damage

MCM8IP activates the MCM8-9 helicase to promote DNA synthesis and homologous recombination upon DNA damage

A genome-wide screening for DNA repair genes: much more players than hitherto known

Ways to unwind with HROB, a new player in homologous recombination

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