Pathway choice in the alternative telomere lengthening in neoplasia is dictated by replication fork processing mediated by EXD2's nuclease activity.

ABSTRACT: Telomerase-independent cancer proliferation via the alternative lengthening of telomeres (ALT) relies upon two distinct, largely uncharacterized, break-induced-replication (BIR) processes. How cancer cells initiate and regulate these terminal repair mechanisms is unknown. Here, we establish that the EXD2 nuclease is recruited to ALT telomeres to direct their maintenance. We demonstrate that EXD2 loss leads to telomere shortening, elevated telomeric sister chromatid exchanges, C-circle formation as well as BIR-mediated telomeric replication. We discover that EXD2 fork-processing activity triggers a switch between RAD52-dependent and -independent ALT-associated BIR. The latter is suppressed by EXD2 but depends specifically on the fork remodeler SMARCAL1 and the MUS81 nuclease. Thus, our find

SUBMITTER: Broderick R 

PROVIDER: S-EPMC10140042 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature