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Schlafen 11 further sensitizes BRCA-deficient cells to PARP inhibitors through single-strand DNA gap accumulation behind replication forks
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Schlafen 11 further sensitizes BRCA-deficient cells to PARP inhibitors through single-strand DNA gap accumulation behind replication forks
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Journal Article
Schlafen 11 further sensitizes BRCA-deficient cells to PARP inhibitors through single-strand DNA gap accumulation behind replication forks
2024
Overview
The preferential response to PARP inhibitors (PARPis) in BRCA-deficient and Schlafen 11 (SLFN11)-expressing ovarian cancers has been documented, yet the underlying molecular mechanisms remain unclear. As the accumulation of single-strand DNA (ssDNA) gaps behind replication forks is key for the lethality effect of PARPis, we investigated the combined effects of SLFN11 expression and BRCA deficiency on PARPi sensitivity and ssDNA gap formation in human cancer cells. PARPis increased chromatin-bound RPA2 and ssDNA gaps in SLFN11-expressing cells and even more in cells with BRCA1 or BRCA2 deficiency. SLFN11 was co-localized with chromatin-bound RPA2 under PARPis treatment, with enhanced recruitment in BRCA2-deficient cells. Notably, the chromatin-bound SLFN11 under PARPis did not block replication, contrary to its function under replication stress. SLFN11 recruitment was attenuated by the inactivation of MRE11. Hence, under PARPi treatment, MRE11 expression and BRCA deficiency lead to ssDNA gaps behind replication forks, where SLFN11 binds and increases their accumulation. As ovarian cancer patients who responded (progression-free survival >2 years) to olaparib maintenance therapy had a significantly higher SLFN11-positivity than short-responders (<6 months), our findings provide a mechanistic understanding of the favorable responses to PARPis in SLFN11-expressing and BRCA-deficient tumors. It highlight the clinical implications of SLFN11.
Publisher
Springer Science and Business Media LLC,Nature Publishing Group UK,Nature Publishing Group
Subject
/ 13/31
/ 13/51
/ 14/19
/ 38/109
/ 38/44
/ 82/29
/ 96/34
/ DNA Replication - drug effects
/ DNA, Single-Stranded - genetics
/ DNA, Single-Stranded - metabolism
/ Female
/ Humans
/ Medicine
/ MRE11 Homologue Protein - genetics
/ MRE11 Homologue Protein - metabolism
/ Nuclear Proteins - metabolism
/ Oncology
/ Ovarian Neoplasms - drug therapy
/ Ovarian Neoplasms - genetics
/ Ovarian Neoplasms - metabolism
/ Ovarian Neoplasms - pathology
/ Poly(ADP-ribose) Polymerase Inhibitors - pharmacology
/ Replication Protein A - genetics
