RAD54L regulates replication fork progression and nascent strand degradation in BRCA1/2-deficient cells.

ABSTRACT: RAD54L is a DNA motor protein with critical roles in homologous recombination DNA repair (HR). In vitro , RAD54L was also shown to catalyze the reversal and restoration of model replication forks. Little, however, is known about the role of RAD54L in regulating the dynamics of DNA replication in cells. Here, we show that RAD54L functions as a fork remodeler and restrains the progression of replication forks in human cells. Analogous to HLTF and FBH1, and consistent with a role in fork reversal, RAD54L catalyzes the slowing of fork progression in response to replication stress. In BRCA1/2-deficient cells, RAD54L activity leads to nascent strand DNA degradation, and loss of RAD54L reduces DNA double-strand break formation. Using a separation-of-function mutation, we show that RAD54L-mediated fork restraint depends on its ability to catalyze branch migration. Our results reveal a new role for RAD54L in regulating the dynamics of replication forks in cells and highlight the impact of RAD54L function on the treatment of patients with BRCA1/2-deficient tumors.

SUBMITTER: Uhrig ME 

PROVIDER: S-EPMC10402051 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature