The MCM8/9 complex: A recent recruit to the roster of helicases involved in genome maintenance

Griffin, Wezley C.; Trakselis, Michael A.

doi:10.1016/j.dnarep.2019.02.003

Cited by 45 publications

(51 citation statements)

References 125 publications

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“…Instead, the MCM8-9 complex has been implicated in HR in both mitotic and meiotic cells [11][12][13] . Consistently, MCM8-and MCM9-null female mice are sterile 13,14 and women carrying biallelic mutations in MCM8-9 exhibit Primary Ovarian Insufficiency (POI), a genetic syndrome characterized by reduced reproductive lifespan 15,16 . Furthermore, as a consequence of their role in HR, MCM8-and MCM9deficient cells are particularly sensitive to DNA interstrand crosslinking agents and PARP inhibition 11,12,17 .…”

Section: Main Textmentioning

confidence: 95%

“…As a complex, MCM8IP-MCM8-9 may therefore have higher affinity for ssDNA, which potentially allows for increased transactions on DNA due to reduced dissociation. Alternatively, MCM8IP binding may facilitate a structural transition from a MCM8-9 heterodimer to a heterohexamer, thereby enhancing processivity due to encirclement of ssDNA 15,19 . Lastly, in lieu of enhancing processivity, the RPA molecules that stabilize D-loops may increase the local availability of MCM8-9 through MCM8IP interaction in order to effectively promote continuous D-loop extension and migration.…”

Section: Mcm8ip and The Regulation Of Hrmentioning

confidence: 99%

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Identification of MCM8IP, an interactor of MCM8-9 and RPA1 that promotes homologous recombination and DNA synthesis in response to DNA damage

Huang

Taglialatela

Acharya

et al. 2019

Preprint

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Homologous recombination (HR) mediates the error-free repair of DNA double-strand breaks to maintain genomic stability. HR is carried out by a complex network of DNA repair factors. Here we identify C17orf53/MCM8IP, an OB-fold containing protein that binds ssDNA, as a novel DNA repair factor involved in HR. MCM8IP-deficient 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 identify a direct interaction with MCM8-9, a putative helicase complex mutated in Primary Ovarian Insufficiency, that is crucial for MCM8IP's ability to promote resistance to DNA damaging agents. In addition to its association with MCM8-9, MCM8IP also binds directly to RPA1. We show that the interactions of MCM8IP with both MCM8-9 and RPA are required to maintain replication fork progression in response to treatment with crosslinking agents. Collectively, our work identifies MCM8IP as a key regulator of DNA damage-associated DNA synthesis during DNA recombination and replication.

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Section: Main Textmentioning

confidence: 95%

Section: Mcm8ip and The Regulation Of Hrmentioning

confidence: 99%

Identification of MCM8IP, an interactor of MCM8-9 and RPA1 that promotes homologous recombination and DNA synthesis in response to DNA damage

Huang

Taglialatela

Acharya

et al. 2019

Preprint

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“…MCM8 and MCM9 are recent additions to the roster of DNA helicases involved in HR (Griffin et al 2019). They are members of the ATPases associated with a variety of cellular activities (AAA+) superfamily and the minichromosome maintenance (MCM) family of proteins that includes MCM2-7 as the heterohexameric helicase complex central to the replication fork.…”

Section: Introductionmentioning

confidence: 99%

“…MCM9 contains a unique and large C-terminal extension (CTE) not found in the other MCM family members and can be alternatively spliced to give a shorter MCM9 M isoform that retains the conserved helicase domains but removes the CTE (Jeffries et al 2013). The CTE is a common feature in other HR helicases and is generally considered to be unstructured with scattered putative amino acid motifs that can impact protein interactions and affect proper function (Griffin et al 2019). However, no such motifs or role for the CTE has been identified for MCM9.…”

Section: Introductionmentioning

confidence: 99%

Motifs of the C-terminal Domain of MCM9 Direct Localization to Sites of Mitomycin-C Damage for RAD51 Recruitment

McKinzey

Gomanthinayagam

Griffin

et al. 2020

Preprint

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The MCM8/9 complex is implicated in aiding fork progression and facilitating homologous recombination (HR) in response to several DNA damage agents. MCM9 itself is an outlier within the MCM family containing a long C-terminal extension (CTE) comprising 42% of the total length, but with no known functional components and high predicted disorder. In this report, we identify and characterize two unique motifs within the primarily unstructured CTE that are required for localization of MCM8/9 to sites of mitomycin C (MMC) induced DNA damage. First, an unconventional ‘bipartite-like’ nuclear localization (NLS) motif consisting of two positively charged amino acid stretches separated by a long intervening sequence is required for the nuclear import of both MCM8 and MCM9. Second, a variant of the BRC motif (BRCv), similar to that found in other HR helicases, is necessary for localization to sites of MMC damage. The MCM9-BRCv directly interacts with and recruits RAD51 downstream to MMC-induced damage to aid in DNA repair. Patient lymphocytes devoid of functional MCM9 and discrete MCM9 knockout cells have a significantly impaired ability to form RAD51 foci after MMC treatment. Therefore, the disordered CTE in MCM9 is functionally important in promoting MCM8/9 activity and in recruiting downstream interactors; thus, requiring full length MCM9 for proper DNA repair.

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“…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).…”

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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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The MCM8/9 complex: A recent recruit to the roster of helicases involved in genome maintenance

Cited by 45 publications

References 125 publications

Identification of MCM8IP, an interactor of MCM8-9 and RPA1 that promotes homologous recombination and DNA synthesis in response to DNA damage

Identification of MCM8IP, an interactor of MCM8-9 and RPA1 that promotes homologous recombination and DNA synthesis in response to DNA damage

Motifs of the C-terminal Domain of MCM9 Direct Localization to Sites of Mitomycin-C Damage for RAD51 Recruitment

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

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