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Nucleic Acids Research 2004 32(17):5249-5259; doi:10.1093/nar/gkh842
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Published online 5 October 2004

Nucleic Acids Research, Vol. 32 No. 17 © Oxford University Press 2004; all rights reserved

DNA double strand break repair in human bladder cancer is error prone and involves microhomology-associated end-joining

Johanne Bentley*, Christine P. Diggle, Patricia Harnden, Margaret A. Knowles and Anne E. Kiltie

Cancer Research UK Clinical Centre, St James's University Hospital, Leeds, LS9 7TF, UK

* To whom correspondence should be addressed. Tel: +44 113 206 4908; Fax: +44 113 242 9886; Email: J.Bentley{at}cancermed.leeds.ac.uk

Received June 18, 2004; Revised and Accepted September 3, 2004

In human cells DNA double strand breaks (DSBs) can be repaired by the non-homologous end-joining (NHEJ) pathway. In a background of NHEJ deficiency, DSBs with mismatched ends can be joined by an error-prone mechanism involving joining between regions of nucleotide microhomology. The majority of joins formed from a DSB with partially incompatible 3' overhangs by cell-free extracts from human glioblastoma (MO59K) and urothelial (NHU) cell lines were accurate and produced by the overlap/fill-in of mismatched termini by NHEJ. However, repair of DSBs by extracts using tissue from four high-grade bladder carcinomas resulted in no accurate join formation. Junctions were formed by the non-random deletion of terminal nucleotides and showed a preference for annealing at a microhomology of 8 nt buried within the DNA substrate; this process was not dependent on functional Ku70, DNA-PK or XRCC4. Junctions were repaired in the same manner in MO59K extracts in which accurate NHEJ was inactivated by inhibition of Ku70 or DNA-PKcs. These data indicate that bladder tumour extracts are unable to perform accurate NHEJ such that error-prone joining predominates. Therefore, in high-grade tumours mismatched DSBs are repaired by a highly mutagenic, microhomology-mediated, alternative end-joining pathway, a process that may contribute to genomic instability observed in bladder cancer.


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