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Project abstract for group bielina
Roles of Mcm10 in DNA Replication and Genome Maintenance
Mcm10 is a multifunctional scaffold protein with reported roles in origin activation, polymerase loading, and replication fork progression. It has been identified as a potent suppressor of replication stress in yeast and human cells, and most recently as a protector of common fragile sites (Miotto et al., 2014). Large-scale synthetic lethality screens with a temperature-sensitive mcm10-1 allele in budding yeast have provided valuable insight into the role that Mcm10 plays in protecting genome integrity (Thu and Bielinsky, 2014).
These researchers hypothesize that multiple ubiquitin-regulated networks, including a novel pathway mediated by the SUMO-targeted ubiquitin ligase (STUbL), Slx5/Slx8 (for synthetically lethal with sgs1), alleviate replication stress when Mcm10's function is compromised. Proteomic analysis of SUMO-conjugates purified from mcm10-1 mutants revealed candidates that are selectively up- or downregulated compared to wild-type cells. The former include homologous recombination proteins Rad52 and Rad59, which are known to be sumoylated in response to replication stress. Among the group of selectively depleted components are members of the chromosomal passenger complex, Bir1 (homolog of human Survivin) and Sli15 (homolog of human INCENP). The reseachers verified that these are bona fide Slx5/Slx8 targets, degradation of which promotes kinetochore detachment to halt progression through mitosis. Thus, SUMO is required to induce cell cycle delay in the face of intrinsic replication stress. In parallel, the researchers have explored the role of human Mcm10 in cell proliferation. Deletion of a single copy of the MCM10 gene causes haploinsufficiency. Unchallenged cells exhibit a significant reduction in origin firing. In contrast, cells treated with replication inhibitors, display problems with replication fork restart. Together, these results suggest that Mcm10 is limiting for DNA replication in human cells.
A bibliography of this group’s publications is attached.
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