| Structural highlights
Disease
[MCM9_HUMAN] 46,XX ovarian dysgenesis-short stature syndrome. The disease is caused by variants affecting the gene represented in this entry.
Function
[MCM9_HUMAN] Component of the MCM8-MCM9 complex, a complex involved in the repair of double-stranded DNA breaks (DBSs) and DNA interstrand cross-links (ICLs) by homologous recombination (HR) (PubMed:23401855). Required for DNA resection by the MRE11-RAD50-NBN/NBS1 (MRN) complex by recruiting the MRN complex to the repair site and by promoting the complex nuclease activity (PubMed:26215093). Probably by regulating the localization of the MRN complex, indirectly regulates the recruitment of downstream effector RAD51 to DNA damage sites including DBSs and ICLs (PubMed:23401855). Acts as a helicase in DNA mismatch repair (MMR) following DNA replication errors to unwind the mismatch containing DNA strand (PubMed:26300262). In addition, recruits MLH1, a component of the MMR complex, to chromatin (PubMed:26300262). The MCM8-MCM9 complex is dispensable for DNA replication and S phase progression (PubMed:23401855). Probably by regulating HR, plays a key role during gametogenesis (By similarity).[UniProtKB:Q2KHI9][1] [2] [3]
Publication Abstract from PubMed
MCM8/9 is a complex involved in homologous recombination (HR) repair pathway. MCM8/9 dysfunction can cause genome instability and result in primary ovarian insufficiency (POI). However, the mechanism underlying these effects is largely unknown. Here, we report crystal structures of the N-terminal domains (NTDs) of MCM8 and MCM9, and build a ring-shaped NTD structure based on a 6.6 A resolution cryoelectron microscopy map. This shows that the MCM8/9 complex forms a 3:3 heterohexamer in an alternating pattern. A positively charged DNA binding channel and a putative ssDNA exit pathway for fork DNA unwinding are revealed. Based on the atomic model, the potential effects of the clinical POI mutants are interpreted. Surprisingly, the zinc-finger motifs are found to be capable of binding an iron atom as well. Overall, our results provide a model for the formation of the MCM8/9 complex and provide a path for further studies.
Structural study of the N-terminal domain of human MCM8/9 complex.,Li J, Yu D, Liu L, Liang H, Ouyang Q, Liu Y Structure. 2021 May 22. pii: S0969-2126(21)00164-7. doi:, 10.1016/j.str.2021.05.006. PMID:34043945[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Park J, Long DT, Lee KY, Abbas T, Shibata E, Negishi M, Luo Y, Schimenti JC, Gambus A, Walter JC, Dutta A. The MCM8-MCM9 complex promotes RAD51 recruitment at DNA damage sites to facilitate homologous recombination. Mol Cell Biol. 2013 Apr;33(8):1632-44. doi: 10.1128/MCB.01503-12. Epub 2013 Feb, 11. PMID:23401855 doi:http://dx.doi.org/10.1128/MCB.01503-12
- ↑ Lee KY, Im JS, Shibata E, Park J, Handa N, Kowalczykowski SC, Dutta A. 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. PMID:26215093 doi:http://dx.doi.org/10.1038/ncomms8744
- ↑ Traver S, Coulombe P, Peiffer I, Hutchins JR, Kitzmann M, Latreille D, Mechali M. MCM9 Is Required for Mammalian DNA Mismatch Repair. Mol Cell. 2015 Sep 3;59(5):831-9. doi: 10.1016/j.molcel.2015.07.010. Epub 2015, Aug 20. PMID:26300262 doi:http://dx.doi.org/10.1016/j.molcel.2015.07.010
- ↑ Li J, Yu D, Liu L, Liang H, Ouyang Q, Liu Y. Structural study of the N-terminal domain of human MCM8/9 complex. Structure. 2021 May 22. pii: S0969-2126(21)00164-7. doi:, 10.1016/j.str.2021.05.006. PMID:34043945 doi:http://dx.doi.org/10.1016/j.str.2021.05.006
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