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Molecular and Cellular Biology, April 2002, p. 2556-2563, Vol. 22, No. 8
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.8.2556-2563.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Central Role for the XRCC1 BRCT I Domain in Mammalian DNA Single-Strand Break Repair

Richard M. Taylor, Angela Thistlethwaite, and Keith W. Caldecott*

School of Biological Sciences, University of Manchester, Manchester M13 9PT, United Kingdom

Received 30 October 2001/ Returned for modification 28 December 2001/ Accepted 16 January 2001

The DNA single-strand break repair (SSBR) protein XRCC1 is required for genetic stability and for embryonic viability. XRCC1 possesses two BRCA1 carboxyl-terminal (BRCT) protein interaction domains, denoted BRCT I and II. BRCT II is required for SSBR during G1 but is dispensable for this process during S/G2 and consequently for cell survival following DNA alkylation. Little is known about BRCT I, but this domain has attracted considerable interest because it is the site of a genetic polymorphism that epidemiological studies have associated with altered cancer risk. We report that the BRCT I domain comprises the evolutionarily conserved core of XRCC1 and that this domain is required for efficient SSBR during both G1 and S/G2 cell cycle phases and for cell survival following treatment with methyl methanesulfonate. However, the naturally occurring human polymorphism in BRCT I supported XRCC1-dependent SSBR and cell survival after DNA alkylation equally well. We conclude that while the BRCT I domain is critical for XRCC1 to maintain genetic integrity and cell survival, the polymorphism does not impact significantly on this function and therefore is unlikely to impact significantly on susceptibility to cancer.

* Corresponding author. Present address: Genome Damage and Stability Centre, University of Sussex, Falmer, Brighton BN1 9RR, United Kingdom. Phone: 01273 678123. Fax: 01273 678121. E-mail: k.w.caldecott{at}sussex.ac.uk.

Molecular and Cellular Biology, April 2002, p. 2556-2563, Vol. 22, No. 8
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.8.2556-2563.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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