Faculty Opinions recommendation of Genetic screens reveal FEN1 and APEX2 as BRCA2 synthetic lethal targets.
Year: 2019
Type: peer-review
Abstract: BRCA1 or BRCA2 inactivation drives hereditary breast and ovarian cancer, but also creates vulnerability to Parp inhibitors.To search for additional targets whose inhibition is synthetically lethal in BRCA2-deficient backgrounds, we screened two pairs of BRCA2 isogenic cell lines with DNA repair-focused shRNA and CRISPR-based libraries.We found BRCA2-deficient cells are selectively dependent on multiple pathways including base excision repair, ATR signaling, and splicing.We identified APEX2 and FEN1 as synthetic lethal genes with both BRCA1 and BRCA2 loss-of-function.BRCA2-deficient cells require the apurinic endonuclease activity and PCNA binding domain of Ape2 (APEX2), but not Ape1 (APEX1).Furthermore, BRCA2-deficient cells require the 5' flap endonuclease but not the 5'-3' exonuclease activity of Fen1, and chemically inhibiting Fen1 selectively targets BRCA-deficient cells.Finally, we developed an MMEJ reporter and showed that Fen1 participates in MMEJ, underscoring the importance of MMEJ as a collateral repair pathway in the context of HR deficiency.
Author: Junjie Chen
Institution: The University of Texas MD Anderson Cancer Center
Language: English
Topic: DNA Repair Mechanisms
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W4239890332