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J. Biol. Chem., Vol. 281, Issue 49, 37517-37526, December 8, 2006

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Evolutionary and Functional Conservation of the DNA Non-homologous End-joining Protein, XLF/Cernunnos^*

Pierre Hentges, Peter Ahnesorg¹, Robert S. Pitcher, Chris K. Bruce^¶, Boris Kysela^¶, Andrew J. Green, Julie Bianchi, Thomas E. Wilson^||, Stephen P. Jackson, and Aidan J. Doherty²

From the Genome Damage and Stability Centre, University of Sussex, Brighton BN1 9RQ, United Kingdom, the Gurdon Institute and Department of Zoology, Cambridge University, Tennis Court Road, Cambridge CB2 1QN, United Kingdom, the ^¶Division of Reproductive and Child Health, Section of Medical and Molecular Genetics, the Medical School, University of Birmingham, Birmingham, B15 2TT, United Kingdom, and the ^||Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109-0602

Non-homologous end-joining is a major pathway of DNA double-strand break repair in mammalian cells, deficiency in which confers radiosensitivity and immune deficiency at the whole organism level. A core protein complex comprising the Ku70/80 heterodimer together with a complex between DNA ligase IV and XRCC4 is conserved throughout eukaryotes and assembles at double-strand breaks to mediate ligation of broken DNA ends. In Saccharomyces cerevisiae an additional NHEJ protein, Nej1p, physically interacts with the ligase IV complex and is required in vivo for ligation of DNA double-strand breaks. Recent studies with cells derived from radiosensitive and immune-deficient patients have identified the human protein, XLF (also named Cernunnos), as a crucial NHEJ protein. Here we show that XLF and Nej1p are members of the same protein superfamily and that this family has members in diverse eukaryotes. Indeed, we show that a member of this family encoded by a previously uncharacterized open-reading frame in the Schizosaccharomyces pombe genome is required for NHEJ in this organism. Furthermore, our data reveal that XLF family proteins can bind to DNA and directly interact with the ligase IV-XRCC4 complex to promote DSB ligation. We therefore conclude that XLF family proteins interact with the ligase IV-XRCC4 complex to constitute the evolutionarily conserved enzymatic core of the NHEJ machinery.

Received for publication, September 11, 2006 , and in revised form, October 10, 2006.

^* This work was supported by grants from BBSRC, AICR, and CR-UK (to A. J. D.) and grants from Cancer Research UK and the European Union (to S. P. J.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S7 and references.

¹ Supported by a Cancer Research UK studentship.

² A Royal Society University Research Fellow. To whom correspondence should be addressed: Genome Damage and Stability Centre, University of Sussex, Brighton BN1 9RQ, UK. Tel.: 44-1273-877-500; Fax: 44-1273-678-121; E-mail: AJD21{at}sussex.ac.uk.

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