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

Kyung Yong Lee, Jun-Sub Im, Etsuko Shibata, Jonghoon Park, Naofumi Handa, Stephen C. Kowalczykowski and Anindya Dutta ()
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Kyung Yong Lee: School of Medicine, University of Virginia
Jun-Sub Im: School of Medicine, University of Virginia
Etsuko Shibata: School of Medicine, University of Virginia
Jonghoon Park: School of Medicine, University of Virginia
Naofumi Handa: University of California
Stephen C. Kowalczykowski: University of California
Anindya Dutta: School of Medicine, University of Virginia

Nature Communications, 2015, vol. 6, issue 1, 1-12

Abstract: Abstract MCM8-9 complex is required for homologous recombination (HR)-mediated repair of double-strand breaks (DSBs). Here we report that MCM8-9 is required for DNA resection by MRN (MRE11-RAD50-NBS1) at DSBs to generate ssDNA. MCM8-9 interacts with MRN and is required for the nuclease activity and stable association of MRN with DSBs. The ATPase motifs of MCM8-9 are required for recruitment of MRE11 to foci of DNA damage. Homozygous deletion of the MCM9 found in various cancers sensitizes a cancer cell line to interstrand-crosslinking (ICL) agents. A cancer-derived point mutation or an SNP on MCM8 associated with premature ovarian failure (POF) diminishes the functional activity of MCM8. Therefore, the MCM8-9 complex facilitates DNA resection by the MRN complex during HR repair, genetic or epigenetic inactivation of MCM8 or MCM9 are seen in human cancers, and genetic inactivation of MCM8 may be the basis of a POF syndrome.

Date: 2015
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DOI: 10.1038/ncomms8744

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