Increased error-prone non homologous DNA end-joining - a proposed mechanism of chromosomal instability in Bloom's Syndrome

Gaymes, Terry J, North, Phillip S, Brady, Nicola, Hickson, Ian D, Mufti, Ghulam J and Rassool, Feyruz (2001) Increased error-prone non homologous DNA end-joining - a proposed mechanism of chromosomal instability in Bloom's Syndrome. Oncogene, 21, pp. 2525-2533. ISSN (print) 0950-9232

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Abstract

BS is an inherited cancer predisposition disorder caused by inactivation of the RecQ family helicase, BLM. One of the defining features of cells from BS individuals is chromosomal instability, characterized by elevated sister chromatid exchanges (SCEs), as well as chromosomal breaks, deletions, and rearrangements. Although the basis for chromosomal instability is poorly understood, there is evidence that chromosomal abnormalities can arise through an alteration in the efficiency or fidelity of DNA double strand break (DSB) repair. Here, we show that BS cells demonstrate aberrant DSB repair mediated by the non-homologous end-joining (NHEJ) pathway for DNA repair, one of the two main pathways for the repair of DSBs in mammalian cells. Through a comparison of BS cell lines, and a derivative in which the BS phenotype has been reverted by expression of the BLM cDNA, we show that BS cells display aberrant end-joining of DSBs. Importantly, DNA end-joining in BS cells is highly error-prone and frequently results in DNA ligation at distant sites of microhomology, creating large DNA deletions. This aberrant repair is dependent upon the presence of the Ku70/86 heterodimer, a key component in the NHEJ pathway. We propose that aberrant NHEJ is a candidate mechanism for the generation of chromosomal instability in BS.

Item Type: Article
Additional Information: This work was supported by the Elimination of Leukaemia Fund and the Imperial Cancer Research Fund.
Research Area: Biological sciences
Cancer studies
Chemistry
Faculty, School or Research Centre: Faculty of Science (until 2011) > School of Life Sciences
Related URLs:
Depositing User: Terry Gaymes
Date Deposited: 25 Aug 2017 13:46
Last Modified: 25 Aug 2017 13:46
URI: http://eprints.kingston.ac.uk/id/eprint/38260

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