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Increased error-prone NHEJ activity in myeloid leukemias is associated with DNA damage at sites that recruit key nonhomologous end-joining proteins

Brady, Nicola, Gaymes, Terry J., Cheung, Manyee, Mufti, Ghulam J. and Rassool, Feyruz V. (2003) Increased error-prone NHEJ activity in myeloid leukemias is associated with DNA damage at sites that recruit key nonhomologous end-joining proteins. Cancer Research, 63(8), pp. 1798-1805. ISSN (print) 0008-5472

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Abstract

Double strand breaks (DSBs) are considered the most lethal form of DNA damage for eukaryotic cells, and misrepair of DSB can cause cell death, chromosome instability, and cancer. Nonhomologous end-joining (NHEJ) is a major mechanism for the repair of DSBs. We previously reported that the cancer predisposition Bloom's syndrome and myeloid leukemias demonstrate increased NHEJ activity and consequent misrepair. In this study, we link this increased NHEJ activity and infidelity to ongoing or induced DNA damage at sites that recruit key NHEJ proteins. We show here that in myeloid leukemia cells and normal hemopoietic cells, agents that induce DSBs produce an up to 2-fold increase in this DSB misrepair activity, whereas an alkylating agent produces little or no increases. Furthermore, NHEJ overactivity after induction of DSBs is dependent on the presence of Ku70/Ku86. We also present data to explain the constitutively activated NHEJ in myeloid leukemias. Using an immunofluorescence-based assay for DNA damage, myeloid leukemias demonstrate constitutive DNA damage in the absence of treatment with DSB-inducing agents compared with normal hemopoietic cells. Importantly, damaged foci from myeloid leukemia and normal cells colocalize with NHEJ proteins Ku70 and Ku86. These data suggest that the generation of increased constitutive DNA damage may be a common pathway for the creation of NHEJ-dependent genomic instability.

Item Type: Article
Research Area: Biological sciences
Cancer studies
Chemistry
Faculty, School or Research Centre: Faculty of Science, Engineering and Computing > School of Life Sciences
Depositing User: Terry Gaymes
Date Deposited: 25 Aug 2017 13:38
Last Modified: 25 Aug 2017 13:38
URI: http://eprints.kingston.ac.uk/id/eprint/38262

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