This old version of Proteopedia is provided for student assignments while the new version is undergoing repairs. Content and edits done in this old version of Proteopedia after March 1, 2026 will eventually be lost when it is retired in about June of 2026.

Apply for new accounts at the new Proteopedia. Your logins will work in both the old and new versions.

7dp3

From Proteopedia

Jump to: navigation, search

Human MCM8 N-terminal domain

Structural highlights

7dp3 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.55Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

MCM8_HUMAN NON RARE IN EUROPE: Primary ovarian failure. The disease is caused by mutations affecting the gene represented in this entry.

Function

MCM8_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 MNR complex, indirectly regulates the recruitment of downstream effector RAD51 to DNA damage sites including DBSs and ICLs (PubMed:23401855). The MCM8-MCM9 complex is dispensable for DNA replication and S phase progression (PubMed:23401855). However, may play a non-essential for DNA replication: may be involved in the activation of the prereplicative complex (pre-RC) during G(1) phase by recruiting CDC6 to the origin recognition complex (ORC) (PubMed:15684404). Probably by regulating HR, plays a key role during gametogenesis (By similarity). Stabilizes MCM9 protein (PubMed:23401855, PubMed:26215093).[UniProtKB:Q9CWV1]^[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

↑ Volkening M, Hoffmann I. Involvement of human MCM8 in prereplication complex assembly by recruiting hcdc6 to chromatin. Mol Cell Biol. 2005 Feb;25(4):1560-8. doi: 10.1128/MCB.25.4.1560-1568.2005. PMID:15684404 doi:http://dx.doi.org/10.1128/MCB.25.4.1560-1568.2005
↑ 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
↑ 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