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Molecular and Cellular Biology, September 2009, p. 4653-4662, Vol. 29, No. 17
0270-7306/09/$08.00+0     doi:10.1128/MCB.00677-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

DNA 3'-Phosphatase Activity Is Critical for Rapid Global Rates of Single-Strand Break Repair following Oxidative Stress{triangledown},{dagger}

Claire Breslin and Keith W. Caldecott*

Genome Damage and Stability Centre, University of Sussex, Falmer, Brighton BN1 9RQ, United Kingdom

Received 26 May 2009/ Accepted 15 June 2009

Oxidative stress is a major source of chromosome single-strand breaks (SSBs), and the repair of these lesions is retarded in neurodegenerative disease. The rate of the repair of oxidative SSBs is accelerated by XRCC1, a scaffold protein that is essential for embryonic viability and that interacts with multiple DNA repair proteins. However, the relative importance of the interactions mediated by XRCC1 during oxidative stress in vivo is unknown. We show that mutations that disrupt the XRCC1 interaction with DNA polymerase β or DNA ligase III fail to slow SSB repair in proliferating CHO cells following oxidative stress. In contrast, mutation of the domain that interacts with polynucleotide kinase/phosphatase (PNK) and Aprataxin retards repair, and truncated XRCC1 encoding this domain fully supports this process. Importantly, the impact of mutating the protein domain in XRCC1 that binds these end-processing factors is circumvented by the overexpression of wild-type PNK but not by the overexpression of PNK harboring a mutated DNA 3'-phosphatase domain. These data suggest that DNA 3'-phosphatase activity is critical for rapid rates of chromosomal SSB repair following oxidative stress, and that the XRCC1-PNK interaction ensures that this activity is not rate limiting in vivo.

* Corresponding author. Mailing address: Genome Damage and Stability Centre, University of Sussex, Falmer, Brighton BN1 9RQ, United Kingdom. Phone: 44 1273 877519. Fax: 44 1279 678121. E-mail: k.w.caldecott{at}sussex.ac.uk

{triangledown} Published ahead of print on 22 June 2009.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, September 2009, p. 4653-4662, Vol. 29, No. 17
0270-7306/09/$08.00+0     doi:10.1128/MCB.00677-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Lu, M., Mani, R. S., Karimi-Busheri, F., Fanta, M., Wang, H., Litchfeld, D. W., Weinfeld, M. (2009). Independent mechanisms of stimulation of polynucleotide kinase/phosphatase by phosphorylated and non-phosphorylated XRCC1. Nucleic Acids Res 0: gkp1023v1-gkp1023 [Abstract] [Full Text]  


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