Depletion of Fumarate Hydratase, an Essential TCA Cycle Enzyme, Drives Proliferation in a Two-Step Model.

ABSTRACT: Fumarate hydratase (FH) is an evolutionary conserved TCA cycle enzyme that reversibly catalyzes the hydration of fumarate to L-malate and has a moonlight function in the DNA damage response (DDR). Interestingly, FH has a contradictory cellular function, as it is pro-survival through its role in the TCA cycle, yet its loss can drive tumorigenesis. Here, we found that in both non-cancerous (HEK-293T) and cancerous cell lines (HepG2), the cell response to FH loss is separated into two distinct time frames based on cell proliferation and DNA damage repair. During the early stages of FH loss, cell proliferation rate and DNA damage repair are inhibited. However, over time the cells overcome the FH loss and form knockout clones, indistinguishable from WT cells with respect to their proliferation

SUBMITTER: Solaimuthu B 

PROVIDER: S-EPMC9688661 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature