Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition.
Deficiency in either of the breast cancer susceptibility proteins BRCA1 or BRCA2 induces profound cellular sensitivity to the inhibition of poly(ADP-ribose) polymerase (PARP) activity. We hypothesized that the critical role of BRCA1 and BRCA2 in the repair of double-strand breaks by homologous recombination (HR) was the underlying reason for this sensitivity. Here, we examine the effects of deficiency of several proteins involved in HR on sensitivity to PARP inhibition. We show that deficiency of RAD51, RAD54, DSS1, RPA1, NBS1, ATR, ATM, CHK1, CHK2, FANCD2, FANCA, or FANCC induces such sensitivity. This suggests that BRCA-deficient cells are, at least in part, sensitive to PARP inhibition because of HR deficiency. These results indicate that PARP inhibition might be a useful therapeutic strategy not only for the treatment of BRCA mutation-associated tumors but also for the treatment of a wider range of tumors bearing a variety of deficiencies in the HR pathway or displaying properties of 'BRCAness.'
McCabe
Nuala
N
Cancer Research UK Gene Function and Regulation Group and The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, United Kingdom.
Turner
Nicholas C
NC
Lord
Christopher J
CJ
Kluzek
Katarzyna
K
Bialkowska
Aneta
A
Swift
Sally
S
Giavara
Sabrina
S
O'Connor
Mark J
MJ
Tutt
Andrew N
AN
Zdzienicka
Małgorzata Z
MZ
Smith
Graeme C M
GC
Ashworth
Alan
A
D000818:Animals; D019313:BRCA1 Protein / Q000235:genetics; D024682:BRCA2 Protein / Q000235:genetics; D004249:DNA Damage; D004260:DNA Repair; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005464:Fluorobenzenes / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D010793:Phthalazines / Q000494:pharmacology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011995:Recombination, Genetic; D013234:Stem Cells / Q000166:cytology
D019313:BRCA1 Protein; D024682:BRCA2 Protein; D004791:Enzyme Inhibitors; D005464:Fluorobenzenes; C506932:KU0058948; D010793:Phthalazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors