Elevated Levels of Mcm7 Disrupt Microtubule and Nucleolar Homeostasis to Drive Genome Instability and Cell Death

Abstract

Overexpression of pre-replication complex (pre-RC) components is frequently associated with poor prognosis in many types of cancer, yet the mechanisms underlying their pathological effects remain unclear. Using the model yeast Candida albicans, we investigated the consequences of elevated Mcm7 levels, a conserved pre-RC subunit previously linked to chromosome instability (CIN). Unlike other pre-RC components, Mcm7 overexpression severely compromises nuclear integrity, resulting in chromatin fragmentation, DNA double-strand breaks, and cell death. Excess Mcm7 disrupts chromosome segregation by impairing microtubule function, disrupting centromere organization, generating abnormal spindle structures, and causing defective nuclear migration, collectively leading to mitotic failure. We further discovered ectopic accumulation of Mcm7 within the nucleolus, accompanied by widespread transcriptional disruption of nucleolus-associated genes. Supporting the relevance of these findings to human disease, cancer transcriptomic datasets reveal a strong association between MCM7 expression and nucleolar gene expression programs, while human cancer cell lines with higher MCM7 expression exhibit increased nucleolar number and size. Together, our findings identify Mcm7 as a previously unrecognized regulator of cytoskeletal and nucleolar homeostasis and uncover an unexpected mechanism by which replication factor dysregulation promotes CIN.