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Nucleic Acids Research 2004 32(18):5609-5620; doi:10.1093/nar/gkh871
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Published online 19 October 2004

Nucleic Acids Research, Vol. 32 No. 18 © Oxford University Press 2004; all rights reserved

Processing of bistranded abasic DNA clusters in {gamma}-irradiated human hematopoietic cells

Alexandros G. Georgakilas1,2, Paula V. Bennett1, David M. Wilson, III3 and Betsy M. Sutherland1,*

1 Biology Department, Brookhaven National Laboratory, Upton, NY 11973-5000, USA, 2 Biology Department, East Carolina University, Greenville, NC 27858-4353, USA and 3 Laboratory of Molecular Gerontology, National Institute of Aging, Baltimore, MD 21224, USA

* To whom correspondence should be addressed. Tel: +1 631 344 3380; Fax: +1 631 344 3407; Email: bms{at}bnl.gov

Received June 28, 2004; Revised and Accepted September 17, 2004

Clustered DNA damages—two or more lesions on opposing strands and within one or two helical turns—are formed in cells by ionizing radiation or radiomimetic antitumor drugs. They are hypothesized to be difficult to repair, and thus are critical biological damages. Since individual abasic sites can be cytotoxic or mutagenic, abasic DNA clusters are likely to have significant cellular impact. Using a novel approach for distinguishing abasic clusters that are very closely spaced (putrescine cleavage) or less closely spaced (Nfo protein cleavage), we measured induction and processing of abasic clusters in 28SC human monocytes that were exposed to ionizing radiation. {gamma}-rays induced ~1 double-strand break: 1.3 putrescine-detected abasic clusters: 0.8 Nfo-detected abasic clusters. After irradiation, the 28SC cells rejoined double-strand breaks efficiently within 24 h. In contrast, in these cells, the levels of abasic clusters decreased very slowly over 14 days to background levels. In vitro repair experiments that used 28SC cell extracts further support the idea of slow processing of specific, closely spaced abasic clusters. Although some clusters were removed by active cellular repair, a substantial number was apparently decreased by ‘splitting’ during DNA replication and subsequent cell division. The existence of abasic clusters in 28SC monocytes, several days after irradiation suggests that they constitute persistent damages that could lead to mutation or cell killing.


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