Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition

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 recom...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Vol. 66; no. 16; pp. 8109 - 8115
Main Authors: MCCABE, Nuala, TURNER, Nicholas C, SMITH, Graeme C. M, ASHWORTH, Alan, LORD, Christopher J, KLUZEK, Katarzyna, BIALKOWSKA, Aneta, SWIFT, Sally, GIAVARA, Sabrina, O'CONNOR, Mark J, TUFT, Andrew N, ZDZIENICKA, Malgorzata Z
Format: Journal Article
Language:English
Published: Philadelphia, PA American Association for Cancer Research 15-08-2006
Subjects:
Animals
Antineoplastic agents
Biological and medical sciences
BRCA1 Protein - genetics
BRCA2 Protein - genetics
DNA Damage
DNA Repair
Embryo, Mammalian
Enzyme Inhibitors - pharmacology
Fluorobenzenes - pharmacology
Medical sciences
Mice
Mice, Knockout
Pharmacology. Drug treatments
Phthalazines - pharmacology
Poly(ADP-ribose) Polymerase Inhibitors
Recombination, Genetic
Stem Cells - cytology
Tumors
Enzyme
Transferases
Deficiency
Homologous recombination
Glycosyltransferases
DNA repair
NAD
Sensitivity
DNA
ADP-ribosyltransferase
Inhibitor
Lesion
Pentosyltransferases
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Summary: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.'
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ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.CAN-06-0140