Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy.
BRCA1 and BRCA2 are important for DNA double-strand break repair by homologous recombination, and mutations in these genes predispose to breast and other cancers. Poly(ADP-ribose) polymerase (PARP) is an enzyme involved in base excision repair, a key pathway in the repair of DNA single-strand breaks. We show here that BRCA1 or BRCA2 dysfunction unexpectedly and profoundly sensitizes cells to the inhibition of PARP enzymatic activity, resulting in chromosomal instability, cell cycle arrest and subsequent apoptosis. This seems to be because the inhibition of PARP leads to the persistence of DNA lesions normally repaired by homologous recombination. These results illustrate how different pathways cooperate to repair damage, and suggest that the targeted inhibition of particular DNA repair pathways may allow the design of specific and less toxic therapies for cancer.
Farmer
Hannah
H
Cancer Research UK Gene Function and Regulation Group, London, UK.
McCabe
Nuala
N
Lord
Christopher J
CJ
Tutt
Andrew N J
AN
Johnson
Damian A
DA
Richardson
Tobias B
TB
Santarosa
Manuela
M
Dillon
Krystyna J
KJ
Hickson
Ian
I
Knights
Charlotte
C
Martin
Niall M B
NM
Jackson
Stephen P
SP
Smith
Graeme C M
GC
Ashworth
Alan
A
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D004260:DNA Repair; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D009154:Mutation / Q000235:genetics*; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D013379:Substrate Specificity; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases