The role of Mcm10 in replication initiation

Minichromosome maintenance protein 10 (Mcm10) is a conserved component of the eukaryotic DNA replication machinery. Mcm10 promotes the initiation of replication by facilitating DNA unwinding and origin firing. Although the molecular details of this action remain unclear, current data support a scaffolding role for Mcm10 via interactions with DNA and other protein partners. Mcm10 binds both single- and double-stranded DNA, as well as components of the CMG helicase complex, DNA polymerase-α, and Ctf4. Upon initiation, Mcm10 becomes part of the replisome, primarily mediating the initiation of Okazaki fragment synthesis, which involves DNA polymerase-α/primase and the replication clamp PCNA. Mcm10 likely contributes to the recruitment of both of these factors. Emerging concepts predict that steady-state levels of Mcm10 are tightly controlled to balance origin firing and fork progression. Investigations into the cellular requirements for Mcm10 have also revealed a key role in maintaining genome stability. Accordingly, it is not surprising that genetic alterations of MCM10 are associated with cancer. Loss of Mcm10 function is a possible source of DNA damage, whereas overexpression of Mcm10 might serve to facilitate rapid DNA synthesis and proliferation. In this chapter, we provide a comprehensive review of the current literature describing Mcm10‘s role in replication initiation. Additionally, we consider how contributions to elongation and other potential functions may affect chromosomal integrity.