MCM8‐9 Complex Promotes Resection of Double‐strand break Ends by Mre11‐Rad50‐Nbs1 Complex

The MCM8‐9 genes were identified because of their homology to the MCM2‐7 genes that encode the DNA replicative‐helicase. Although initial reports suggested that MCM8‐9 are involved in the licensing of origins or replication elongation, we find that mammalian cells can be depleted of the two proteins without any effect on DNA replication or S phase progression. Indeed, mice null for MCM9 have been created by John Schimenti's group. Instead of a role in DNA replication, MCM8‐9 complex is required for repair of DNA interstrand crosslinks (ICLs) and Homologous Recombination (HR)‐mediated repair of double‐strand breaks (DSBs) at a stage prior to the recruitment of Rad51 to the sites of DNA damage. DNA resection at double‐strand‐breaks to generate ssDNA and the subsequent recruitment of RPA to these sites is impeded by deficiency of MCM8 or MCM9.MCM8‐9 interacts with the MRN (MRE11‐RAD50‐NBS1) complex and stimulates its nuclease activity and stable association with DNA damage sites. The ATPase motifs of MCM8‐9 are required for recruitment of MRE11 to foci of DNA damage to make RPA foci. Mutations in the ATPase motifs of MCM9 disrupt its interaction with MRE11, and inhibit the localization of MRE11 to DSB sites. Interestingly, homozygous deletion or point mutations of the MCM9 locus is found in various cancers (e.g., 6‐7% of prostate adenocarcinoma, salivary adenoid‐cystic carcinoma, etc.) and sensitize a cancer cell‐line to ICL reagents. A naturally occurring SNP on MCM8 is associated with premature ovarian failure (POF) and diminishes the functional activity of MCM8. Therefore, the MCM8‐9 complex facilitates DNA resection by the MRN complex during HR repair, and genetic or epigenetic inactivation of MCM8 or MCM9 are seen in human cancers and explain the genetic basis of a POF syndrome.