RPA exhaustion activates SLFN11 to eliminate cells with heightened replication stress.

ABSTRACT: SLFN11 is epigenetically silenced and confers chemoresistance in half of all cancers. In response to replication stress, SLFN11 triggers translation shutdown and p53-independent apoptosis, but how DNA damage activates SLFN11 remains unclear. Here through CRISPR-based screens we implicate SLFN11 as the critical determinant of cisplatin sensitivity in cells lacking primase-polymerase (PrimPol)-mediated repriming. SLFN11 and the downstream integrated stress response uniquely promote cisplatin-driven apoptosis in PrimPol-deficient cells. We demonstrate that replication protein A (RPA) exhaustion and single-stranded DNA exposure trigger SLFN11 activation and cell death when PrimPol is inactivated. We further identify the USP1-WDR48 deubiquitinase complex as a positive modulator of SLFN11 activa

SUBMITTER: Stanage TH 

PROVIDER: S-EPMC12904793 | biostudies-literature | 2026 Feb

REPOSITORIES: biostudies-literature