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

Nat Commun. 2015 Jul 28;6:7744. doi: 10.1038/ncomms8744.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • ATP-Binding Cassette Transporters / metabolism
  • Acid Anhydride Hydrolases
  • Animals
  • Carrier Proteins / metabolism
  • Cell Cycle Proteins / metabolism*
  • Chromatin Immunoprecipitation
  • DNA Breaks, Double-Stranded*
  • DNA Damage
  • DNA Repair
  • DNA Repair Enzymes / metabolism*
  • DNA, Single-Stranded
  • DNA-Binding Proteins / metabolism*
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • MRE11 Homologue Protein
  • Mice
  • Minichromosome Maintenance Proteins / metabolism*
  • Nuclear Proteins / metabolism*
  • Recombinational DNA Repair
  • Tumor Suppressor Proteins / metabolism
  • Xenopus
  • Xenopus Proteins / metabolism

Substances

  • ATP-Binding Cassette Transporters
  • Carrier Proteins
  • Cell Cycle Proteins
  • DNA, Single-Stranded
  • DNA-Binding Proteins
  • MRE11 protein, human
  • Mre11 protein, Xenopus
  • Mre11a protein, mouse
  • NBN protein, Xenopus
  • NBN protein, human
  • Nijmegen breakage syndrome 1 protein, mouse
  • Nuclear Proteins
  • Rad50 protein, Xenopus
  • Tumor Suppressor Proteins
  • Xenopus Proteins
  • MRE11 Homologue Protein
  • Acid Anhydride Hydrolases
  • Rad50 protein, human
  • Rad50 protein, mouse
  • MCM8 protein, Xenopus
  • MCM8 protein, human
  • MCM9 protein, Xenopus
  • MCM9 protein, human
  • Mcm8 protein, mouse
  • Mcm9 protein, mouse
  • Minichromosome Maintenance Proteins
  • DNA Repair Enzymes