SLFN11 Blocks DNA Replication Independently of ATR Activity

The Schlafen family protein 11 (SLFN11), which is frequently inactivated in cancer cell lines, has been shown to sensitize cancer cells to anticancer drugs. In particular, elevated SLFN11 expression is associated with sensitivity to DNA-damaging agents which concurrently promote replication fork stalling and cell cycle checkpoint activation, and induce replication stress. Having recently shown that PARP inhibitor (PARPi) treatment results in SLFN11-mediated lethal prolonged S-phase arrest, Murai and colleagues sought to elucidate the mechanism by which SLFN11 inhibits replication. Treatment of isogenic leukemia cell lines (parental and SLFN11-deleted) with camptothecin, a topoisomerase inhibitor that induces DNA breaks at replication forks and activates the ATR-mediated S-phase checkpoint, showed that SLFN11 inhibits DNA replication and promotes apoptosis independently of ATR in response to replication stress. Specifically, it was shown that the ATP hydrolysis domain of SLFN11 was required for SLFN11-driven replication inhibition and cell death. Further, camptothecin treatment promoted the replication protein A1 (RPA1)–mediated recruitment of SLFN11 to replication foci and the interaction of SLFN11 with the DNA helicases DHX9 and MCM3, resulting in the inhibition of replication predominantly during mid-to-late S-phase regardless of ATR activity. The binding of SLFN11 to chromatin in response to camptothecin treatment prevented replication foci formation independently of the loading of CDC45 and PCNA to chromatin, which is essential for replication initiation and is inhibited by ATR/CHK1, and blocked RPA extension. Mechanistically, DNA damage–induced replication stress promotes the binding of SLFN11 to chromatin, resulting in the ATPase-dependent chromatin opening near initiation sites and inhibition of replication. Similarly, CHK1 inhibition with prexasertib induced the binding of SLFN11 to stressed replication forks and SLFN11-mediated replication inhibition. Together, these results provide insight into the chemosensitization of cancer cells by SLFN11 and suggest that SLFN11 may be a potential tumor suppressor.

Murai J, Tang SW, Leo E, Baechler SA, Redon CE, Zhang H, Abo MA, et al. SLFN11 blocks stressed replication forks independently of ATR. Mol Cell 2018;69:371–84.

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