Characterization of MCM8/9 in DNA repair.


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MCM8 and MCM9 are recent additions to the minichromosomal maintenance family (MCM) of DNA helicases. While not directly implicated in replication, they show both a protective role in aiding the replication fork and assisting in various aspects of DNA repair. The previously uncharacterized C-terminal extension of MCM9 serves vital roles directing the MCM8/9 complex to the nucleus using a bipartite-like nuclear localization sequence (NLS) and promoting interacts with RAD51 through an identified BRC variant (BRCv) motif. Loss of MCM8/9 slows the overall replication speed resulting from more transient fork reversal, lack of protection of the nascent strand, and ultimately double strand breaks. Finally, enzymatic and structural characterization of MCM8/9 reveals a clear affinity for ssDNA containing substrates, stable protection from nucleases, DNA stimulated ATPase activity, and a preferred unwinding orientation. Using cryo-EM, a Walker B mutant version of the MCM8/9 complex shows the overall hexameric structure with the strong density for the C-terminal ATPase domain bound to nucleotide. Altogether this work shows the structure/function activity of the MCM8/9 complex for a more complete understanding of the importance and impact of this complex to maintain genomic integrity during DNA replication.