1. Cancer Research UK Gene Function and Regulation Group and
2. The Breakthrough Breast Cancer Research Centre Institute of Cancer Research, Fulham Road, London SW3 6JB, UK
3. Guy's Hospital, St Thomas' Street, London SE1 9RT, UK
4. KuDOS Pharmaceuticals Ltd, Cambridge Science Park, Cambridge CB4 0WG, UK
5. Wellcome Trust and Cancer Research UK, Gurdon Institute of Cancer and Developmental Biology, and Department of Zoology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK
6. These authors contributed equally to this work
7. Present address: Division of Experimental Oncology1, CRO-IRCCS, Aviano 33081 PN, Italy

Correspondence to: Graeme C. M. Smith⁴Alan Ashworth^1,2 Correspondence and requests for materials should be addressed to A.A. (Email: alan.ashworth@icr.ac.uk) or G.C.M.S. (Email: gcmsmith@kudospharma.co.uk).

Abstract

BRCA1 and BRCA2 are important for DNA double-strand break repair by homologous recombination¹, and mutations in these genes predispose to breast and other cancers². Poly(ADP-ribose) polymerase (PARP) is an enzyme involved in base excision repair, a key pathway in the repair of DNA single-strand breaks³. 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.

1. Cancer Research UK Gene Function and Regulation Group and
2. The Breakthrough Breast Cancer Research Centre Institute of Cancer Research, Fulham Road, London SW3 6JB, UK
3. Guy's Hospital, St Thomas' Street, London SE1 9RT, UK
4. KuDOS Pharmaceuticals Ltd, Cambridge Science Park, Cambridge CB4 0WG, UK
5. Wellcome Trust and Cancer Research UK, Gurdon Institute of Cancer and Developmental Biology, and Department of Zoology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK
6. These authors contributed equally to this work
7. Present address: Division of Experimental Oncology1, CRO-IRCCS, Aviano 33081 PN, Italy

Correspondence to: Graeme C. M. Smith⁴Alan Ashworth^1,2 Correspondence and requests for materials should be addressed to A.A. (Email: alan.ashworth@icr.ac.uk) or G.C.M.S. (Email: gcmsmith@kudospharma.co.uk).

MORE ARTICLES LIKE THIS

These links to content published by NPG are automatically generated.