Mcm8 and Mcm9 Form a Complex that Functions in Homologous Recombination Repair Induced by DNA Interstrand Crosslinks

Nishimura, Kohei; Ishiai, Masamichi; Horikawa, Kazuki; Fukagawa, Tatsuo; Takata, Minoru; Takisawa, Haruhiko; Kanemaki, Masato T.

doi:10.1016/j.molcel.2012.05.047

Cited by 126 publications

(154 citation statements)

References 53 publications

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“…Lutzmann et al reported that MCM8-9 knockout mice showed defects in gametogenesis and were sensitive to DSBs (45). Nishimura et al reported a role for MCM8-9 in HR using chicken DT40 cells (46). Although these two reports suggest a role of MCM8-9 in HR, they propose different roles for MCM8-9 in this process.…”

Section: Discussionmentioning

confidence: 99%

The MCM8-MCM9 Complex Promotes RAD51 Recruitment at DNA Damage Sites To Facilitate Homologous Recombination

Park

Long

Lee³

et al. 2013

Molecular and Cellular Biology

106

122

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eThe minichromosome maintenance protein homologs MCM8 and MCM9 have previously been implicated in DNA replication elongation and prereplication complex (pre-RC) formation, respectively. We found that MCM8 and MCM9 physically associate with each other and that MCM8 is required for the stability of MCM9 protein in mammalian cells. Depletion of MCM8 or MCM9 in human cancer cells or the loss of function MCM9 mutation in mouse embryo fibroblasts sensitizes cells to the DNA interstrand cross-linking (ICL) agent cisplatin. Consistent with a role in the repair of ICLs by homologous recombination (HR), knockdown of MCM8 or MCM9 significantly reduces HR repair efficiency. Chromatin immunoprecipitation analysis using human DR-GFP cells or Xenopus egg extract demonstrated that MCM8 and MCM9 proteins are rapidly recruited to DNA damage sites and promote RAD51 recruitment. Thus, these two metazoan-specific MCM homologs are new components of HR and may represent novel targets for treating cancer in combination with DNA cross-linking agents. Homologous recombination (HR) is critical for the repair of DNA damage induced by endogenous or exogenous agents. For example, ionizing radiation or the DNA-damaging agent doxorubicin induces double-stranded DNA breaks (DSBs) that are repaired by HR and nonhomologous end joining (NHEJ) (1). On the other hand, the repair of DNA interstrand cross-links (ICLs), induced by cisplatin, or by natural cellular metabolites such as lipid peroxides (2) usually occurs during the S phase of the cell cycle of proliferating cells (3, 4) and is dependent on translesion DNA synthesis (TLS), followed by HR (4-6). Several proteins, including the Fanconi anemia-related proteins (3, 7) and structure-specific endonucleases such as FAN1 (8-10), MUS81-EME1 (11), XPF-ERCC1 (12), and SLX1-SLX4 (13), as well as translesion DNA polymerases (4, 6) and HR-related proteins (5), are essential for the repair of ICLs.HR consists of three steps: presynapsis, synapsis, and postsynapsis (1). During presynapsis, the MRN complex (MRE11, RAD50, and NBS1) interacts with CtIP (14, 15) and recognizes DNA breaks to make a short 3= overhang structure. In yeast, the SGS1-DNA2 helicase/nuclease complex, as well as exonuclease 1 (EXO1), further resect the DNA ends to produce extended 3= overhangs (16). Protein-protein interaction studies and in vitro assays suggest that the human BLM helicase may function as an ortholog of SGS1 (17), but it remains unclear whether BLM promotes the DNA resection step in vivo. After DNA resection, the RPA single-stranded DNA-binding protein is recruited to singlestranded DNA to stabilize the structure, and mediator proteins, including RAD51C, RAD52, and BRCA2, promote the formation of a RAD51 filament. RAD51, a key element in HR, binds singlestranded DNA at DNA breaks and facilitates the search for a homology donor (18). During the synapsis stage, strand invasion makes the D-loop, followed by RAD51 displacement, to promote DNA synthesis. Branch migration occurs during the postsynapsis stage, and the repair...

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Section: Discussionmentioning

confidence: 99%

The MCM8-MCM9 Complex Promotes RAD51 Recruitment at DNA Damage Sites To Facilitate Homologous Recombination

Park

Long

Lee³

et al. 2013

Molecular and Cellular Biology

106

122

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“…To obtain stably expressing clones, chRFWD3-IRES-GFP-or GFPchRFWD3-expressing plasmids were transfected into ΔRFWD3 DT40 cells. Clones were selected by measurement of GFP expression levels on a FACSCalibur (Becton Dickinson) flow cytometer (25,47).…”

Section: Methodsmentioning

confidence: 99%

Biallelic mutations in the ubiquitin ligase RFWD3 cause Fanconi anemia

Knies¹,

Inano²,

Ramı́rez³

et al. 2017

Journal of Clinical Investigation

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168

156

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The WD40-containing E3 ubiquitin ligase RFWD3 has been recently linked to the repair of DNA damage by homologous recombination (HR). Here we have shown that an RFWD3 mutation within the WD40 domain is connected to the genetic disease Fanconi anemia (FA). An individual presented with congenital abnormalities characteristic of FA. Cells from the patient carrying the compound heterozygous mutations c.205_206dupCC and c.1916T>A in RFWD3 showed increased sensitivity to DNA interstrand cross-linking agents in terms of increased chromosomal breakage, reduced survival, and cell cycle arrest in G 2 phase. The cellular phenotype was mirrored in genetically engineered human and avian cells by inactivation of RFWD3 or introduction of the patient-derived missense mutation, and the phenotype was rescued by expression of wild-type RFWD3 protein. HR was disrupted in RFWD3-mutant cells as a result of impaired relocation of mutant RFWD3 to chromatin and defective physical interaction with replication protein A. Rfwd3 knockout mice appear to have increased embryonic lethality, are subfertile, show ovarian and testicular atrophy, and have a reduced lifespan resembling that of other FA mouse models. Although RFWD3 mutations have thus far been detected in a single child with FA, we propose RFWD3 as an FA gene, FANCW, supported by cellular paradigm systems and an animal model.

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“…Two additional MCM family members, Mcm8 and Mcm9, which contain an MCM box, were identified in higher eukaryotes (20 -23). Mcm8 and Mcm9 work downstream of the Fanconi anemia and BRCA2/Rad51 pathways and are required for homologous recombination, which promotes sister chromatid exchange (24,25). MCM-binding protein (MCM-BP) was first identified as a protein that strongly associates with human MCM proteins.…”

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confidence: 99%

The Fission Yeast Minichromosome Maintenance (MCM)-binding Protein (MCM-BP), Mcb1, Regulates MCM Function during Prereplicative Complex Formation in DNA Replication

Santosa

Martha

Hirose

et al. 2013

Journal of Biological Chemistry

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Background: MCM-BP is a novel binding partner of the MCM complex; the mechanisms by which MCM-BP functions and associates with MCM complexes are not well understood. Results: Genetic analysis showed that mcb1 ts mutants exercise defective regulation of prereplicative MCM complex formation during DNA replication. Conclusion:Mcb1 regulates MCM function during prereplicative complex formation in DNA replication. Significance: This study presents the first evidence of MCM-BP function during prereplicative complex formation.

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Mcm8 and Mcm9 Form a Complex that Functions in Homologous Recombination Repair Induced by DNA Interstrand Crosslinks

Cited by 126 publications

References 53 publications

The MCM8-MCM9 Complex Promotes RAD51 Recruitment at DNA Damage Sites To Facilitate Homologous Recombination

The MCM8-MCM9 Complex Promotes RAD51 Recruitment at DNA Damage Sites To Facilitate Homologous Recombination

Biallelic mutations in the ubiquitin ligase RFWD3 cause Fanconi anemia

The Fission Yeast Minichromosome Maintenance (MCM)-binding Protein (MCM-BP), Mcb1, Regulates MCM Function during Prereplicative Complex Formation in DNA Replication

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