Journal
DNA REPAIR
Volume 7, Issue 8, Pages 1399-1406Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.dnarep.2008.04.017
Keywords
DNA glycosylase; cross-link repair; gamma-H2AX foci; psoralen; base excision repair
Categories
Funding
- NCI NIH HHS [R01 CA075576, CA 055042, CA 075576, R01 CA055042] Funding Source: Medline
- NIEHS NIH HHS [P30 ES002109, ES 02109] Funding Source: Medline
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DNA interstrand cross-links (ICLs), widely used in chemotherapy, are cytotoxic lesions because they block replication and transcription. Repair of ICLs involves proteins from different repair pathways however the precise mechanism is still not completely understood. Here, we report that the 3-methyladenine DNA glycosylase (Aag), an enzyme that initiates base excision repair at a variety of alkylated bases, is also involved in the repair of ICLs. Aag-/- mouse embryonic stem cells were shown to be more sensitive to the cross-linking agent 4,S',8-trimethylpsoralen than wild-type cells, but no more sensitive than wild-type to the psoralen derivative Angelicin that forms only monoadducts. We show that -y-H2AX foci formation, a marker for double strand breaks that are formed during ICL repair, is impaired in psoralen treated Aay-/- cells in both quantity and kinetics. However, in our in vitro system, purified human AAG can neither bind to the ICL nor cleave it. Taken together, our results suggest that Aag is important for the resistance of mouse ES cells to psoralen- induced ICLs. (c) 2008 Elsevier B.V All rights reserved.
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