Genetic Screens Reveal FEN1 and APEX2 as BRCA2 Synthetic Lethal Targets

BRCA1 or BRCA2 inactivation drives breast and ovarian cancer but also creates vulnerability to poly(ADP-ribose) polymerase (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 w...

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Veröffentlicht in:Molecular cell Jg. 73; H. 5; S. 885
Hauptverfasser: Mengwasser, Kristen E, Adeyemi, Richard O, Leng, Yumei, Choi, Mei Yuk, Clairmont, Connor, D'Andrea, Alan D, Elledge, Stephen J
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States 07.03.2019
Schlagworte:
Ataxia Telangiectasia Mutated Proteins - genetics
Ataxia Telangiectasia Mutated Proteins - metabolism
BRCA1 Protein - genetics
BRCA1 Protein - metabolism
BRCA2 Protein - genetics
BRCA2 Protein - metabolism
Cell Death
Cell Line, Tumor
CRISPR-Cas Systems
DNA Damage
DNA End-Joining Repair
DNA-(Apurinic or Apyrimidinic Site) Lyase - genetics
DNA-(Apurinic or Apyrimidinic Site) Lyase - metabolism
Flap Endonucleases - genetics
Flap Endonucleases - metabolism
Gene Expression Regulation, Neoplastic
Genes, Lethal
Humans
Neoplasms - drug therapy
Neoplasms - enzymology
Neoplasms - genetics
Neoplasms - pathology
Poly(ADP-ribose) Polymerase Inhibitors - pharmacology
Proliferating Cell Nuclear Antigen - genetics
Proliferating Cell Nuclear Antigen - metabolism
Protein Binding
Protein Interaction Domains and Motifs
RNA Interference
RNA, Small Interfering - genetics
Synthetic Lethal Mutations
MMEJ
FEN1
synthetic lethality
APEX2
PARP
BRCA1
NHEJ
BRCA2
BER
ATR
ISSN:1097-4164, 1097-4164
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Zusammenfassung:BRCA1 or BRCA2 inactivation drives breast and ovarian cancer but also creates vulnerability to poly(ADP-ribose) polymerase (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 small hairpin RNA (shRNA) and CRISPR (clustered regularly interspaced short palindromic repeats)-based libraries. We found that 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 the 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 a microhomology-mediated end-joining (MMEJ) reporter and showed that Fen1 participates in MMEJ, underscoring the importance of MMEJ as a collateral repair pathway in the context of homologous recombination (HR) deficiency.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:1097-4164
1097-4164
DOI:10.1016/j.molcel.2018.12.008