A cancer-associated polymorphism in ESCRT-III disrupts the abscission checkpoint and promotes genome instability.

ABSTRACT: Cytokinetic abscission facilitates the irreversible separation of daughter cells. This process requires the endosomal-sorting complexes required for transport (ESCRT) machinery and is tightly regulated by charged multivesicular body protein 4C (CHMP4C), an ESCRT-III subunit that engages the abscission checkpoint (NoCut) in response to mitotic problems such as persisting chromatin bridges within the midbody. Importantly, a human polymorphism in CHMP4C (rs35094336, CHMP4C^T232) increases cancer susceptibility. Here, we explain the structural and functional basis for this cancer association: The CHMP4C^T232 allele unwinds the C-terminal helix of CHMP4C, impairs binding to the early-acting ESCRT factor ALIX, and disrupts the abscission checkpoint. Cells expressing CHMP4C

SUBMITTER: Sadler JBA 

PROVIDER: S-EPMC6156662 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature