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Orchestration of base excision repair by controlling the rates of enzymatic activities.

Allinson, Sarah L. and Sleeth, Kate M. and Matthewman, Gemma E. and Dianov, Grigory L. (2004) Orchestration of base excision repair by controlling the rates of enzymatic activities. DNA Repair, 3 (1). pp. 23-31. ISSN 1568-7864

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Abstract

Base excision repair (BER) is one of the major pathways for repair of simple DNA base lesions and is carried out through a series of coordinated reactions relying on several different enzymatic activities and accessory proteins. Imbalance of BER activities has been reported to be linked to genetic instability and cancer. To experimentally address the mechanisms orchestrating BER, we monitored both the overall rate and the rate-limiting steps in the repair in cell-free extracts of five different endogenously occurring DNA lesions (abasic site, uracil, 8-oxoguanine, hypoxanthine and 5,6-dihydrouracil) and the effect of addition of rate-limiting BER components on the rate and co-ordination of BER reactions. We find that several mechanisms including regulation of DNA glycosylase turnover and involvement of poly(ADP-ribose) polymerase participate in synchronization of the repair events. We also find that repair of different DNA lesions involves different mechanisms for optimizing repair rates without accumulation of intermediates. Repair of some lesions such as 8-oxoguanine is regulated by glycosylase turnover and progress without substantial accumulation of repair intermediates. However, during repair of the apurinic/apyrimidinic (AP) sites or 5,6-dihydrouracil, poly(ADP-ribose) polymerase plays an important role in the coordination of the rates of repair reactions.

Item Type: Article
Journal or Publication Title: DNA Repair
Uncontrolled Keywords: Base lesions ; Base excision repair ; Human cell extracts ; Pol β ; AP endonuclease ; PARP
Subjects: Q Science > QH Natural history > QH301 Biology
Departments: Faculty of Health and Medicine > Biomedical & Life Sciences
ID Code: 10160
Deposited By: Dr Sarah Allinson
Deposited On: 08 Jul 2008 13:06
Refereed?: Yes
Published?: Published
Last Modified: 17 Sep 2013 10:47
Identification Number:
URI: http://eprints.lancs.ac.uk/id/eprint/10160

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