MCM8-9 complex promotes resection of double-strand break ends by MRE11-RAD50-NBS1 complex

Lee, Kyung Yong; Im, Jun Sub; Shibata, Etsuko; Park, Jonghoon; Handa, Nobuhiko; Kowalczykowski, Stephen C.; Dutta, Anindya

doi:10.1038/ncomms8744

Cited by 91 publications

(94 citation statements)

References 43 publications

(41 reference statements)

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“…The immunofluorescence was performed as previously described (Lee et al, 2015). U2OS or HeLa DR13-9 cells were grown on coverslips, washed with PBS twice, and fixed with 4% paraformaldehyde with 0.1 % Triton X-100 for 10 min.…”

Section: Methods Detailsmentioning

confidence: 99%

ASF1a Promotes Non-homologous End Joining Repair by Facilitating Phosphorylation of MDC1 by ATM at Double-Strand Breaks

Lee

Shibata

et al. 2017

Molecular Cell

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Summary Double strand breaks (DSBs) of the DNA in eukaryotic cells are predominantly repaired by non-homologous end joining (NHEJ). The histone chaperone, anti-silencing factor 1a (ASF1a) interacts with MDC1 and is recruited to sites of DSB to facilitate the interaction of phospho-ATM with MDC1 and the phosphorylation of MDC1, which is required for the recruitment of RNF8/RNF168 histone ubiquitin ligases. Thus, ASF1a deficiency reduces histone ubiquitination at DSBs, decreasing the recruitment of 53BP1 and decreases NHEJ, rendering cells more sensitive to DSBs. This role of ASF1a in DSB repair cannot be provided by the closely related ASF1b, and does not require its histone chaperone activity. Homozygous deletion of ASF1a is seen in 10-15% of certain cancers, suggesting that loss of NHEJ may be selected in some malignancies, and that the deletion can be used as a molecular biomarker for cancers susceptible to radiotherapy or to DSB-inducing chemotherapy.

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Section: Methods Detailsmentioning

confidence: 99%

ASF1a Promotes Non-homologous End Joining Repair by Facilitating Phosphorylation of MDC1 by ATM at Double-Strand Breaks

Lee

Shibata

et al. 2017

Molecular Cell

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“…MCM8 and MCM9 function in DNA repair and homologous recombination (Park et al 2013;Traver et al 2015). Both are dispensable for DNA replication in mice, but MCM8-and MCM9-deficient cells exhibit defects in homologous recombination repair in response to DNA damage (Hartford et al 2011;Lutzmann et al 2012;Nishimura et al 2012;Park et al 2013;Lee et al 2015;Luo and Schimenti 2015). Surprisingly, Mcm9, which is absent from Drosophila, is also required for DNA mismatch repair and this may actually be its primary function (Traver et al 2015).…”

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confidence: 99%

Repair of Meiotic DNA Breaks and Homolog Pairing in Mouse Meiosis Requires a Minichromosome Maintenance (MCM) Paralog

McNairn¹,

Rinaldi²,

Schimenti

2017

Genetics

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The mammalian Mcm-domain containing 2 (Mcmdc2) gene encodes a protein of unknown function that is homologous to the minichromosome maintenance family of DNA replication licensing and helicase factors. Drosophila melanogaster contains two separate genes, the Mei-MCMs, which appear to have arisen from a single ancestral Mcmdc2 gene. The Mei-MCMs are involved in promoting meiotic crossovers by blocking the anticrossover activity of BLM helicase, a function presumably performed by MSH4 and MSH5 in metazoans. Here, we report that MCMDC2-deficient mice of both sexes are viable but sterile. Males fail to produce spermatozoa, and formation of primordial follicles is disrupted in females. Histology and immunocytological analyses of mutant testes revealed that meiosis is arrested in prophase I, and is characterized by persistent meiotic double-stranded DNA breaks (DSBs), failure of homologous chromosome synapsis and XY body formation, and an absence of crossing over. These phenotypes resembled those of MSH4/5-deficient meiocytes. The data indicate that MCMDC2 is essential for invasion of homologous sequences by RAD51-and DMC1-coated single-stranded DNA filaments, or stabilization of recombination intermediates following strand invasion, both of which are needed to drive stable homolog pairing and DSB repair via recombination in mice.

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“…Recent studies suggest that MCM8 is recruited to the DNA repair site to facilitate DNA homologous recombination and double-strand breaks(44, 45). Genome instability was identified in mice that are deficient in MCM8(46).…”

Section: Discussionmentioning

confidence: 99%

Oncogenic activity of amplified miniature chromosome maintenance 8 in human malignancies

et al. 2017

Oncogene

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Miniature chromosome maintenance (MCM) proteins play critical roles in DNA replication licensing, initiation and elongation. MCM8, one of the MCM proteins playing a critical role in DNA repairing and recombination, was found to have over-expression and increased DNA copy number in a variety of human malignancies. The gain of MCM8 is associated with aggressive clinical features of several human cancers. Increased expression of MCM8 in prostate cancer is associated with cancer recurrence. Forced expression of MCM8 in RWPE1 cells, the immortalized but non-transformed prostate epithelial cell line, exhibited fast cell growth and transformation, while knocked down of MCM8 in PC3, DU145 and LNCaP cells induced cell growth arrest, and decreased tumor volumes and mortality of severe combined immunodeficiency mice xenografted with PC3 and DU145 cells. MCM8 bound cyclin D1 and activated Rb protein phosphorylation by cyclin-dependent kinase 4 in vitro and in vivo. The cyclin D1/MCM8 interaction is required for Rb phosphorylation and S phase entry in cancer cells. As a result, our study showed that copy number increase and overexpression of MCM8 may play critical roles in human cancer development.

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MCM8-9 complex promotes resection of double-strand break ends by MRE11-RAD50-NBS1 complex

Cited by 91 publications

References 43 publications

ASF1a Promotes Non-homologous End Joining Repair by Facilitating Phosphorylation of MDC1 by ATM at Double-Strand Breaks

ASF1a Promotes Non-homologous End Joining Repair by Facilitating Phosphorylation of MDC1 by ATM at Double-Strand Breaks

Repair of Meiotic DNA Breaks and Homolog Pairing in Mouse Meiosis Requires a Minichromosome Maintenance (MCM) Paralog

Oncogenic activity of amplified miniature chromosome maintenance 8 in human malignancies

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