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J. Biol. Chem., Vol. 279, Issue 37, 38409-38414, September 10, 2004

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Homo-oligomerization Is the Essential Function of the Tandem BRCT Domains in the Checkpoint Protein Crb2^*

Li-Lin Du, Bettina A. Moser, and Paul Russell¶

From the Departments of Molecular Biology and Cell Biology, The Scripps Research Institute, La Jolla, California 92037

BRCT (BRCA1 C terminus) domains are frequently found as a tandem repeat in proteins involved in DNA damage responses, such as Saccharomyces cerevisiae Rad9, human 53BP1 and BRCA1. Tandem BRCT domains mediate protein-protein and protein-DNA interactions. However, the functional significance of these interactions is largely unknown. Here we report the oligomerization of Schizosaccharomyces pombe checkpoint protein Crb2 through its tandem BRCT domains. Truncated Crb2 without BRCT domains is defective in DNA damage checkpoint signaling. However, addition of either of two heterologous dimerization motifs largely restores the functions of truncated Crb2 without BRCT domains. Replacement of Crb2 BRCT domains with a dimerization motif also renders cells resistant to the dominant negative effect of overexpressing Crb2 BRCT domains. These results demonstrate that the crucial function of the tandem BRCT domains is to oligomerize Crb2.

Received for publication, March 25, 2004 , and in revised form, June 28, 2004.

^* This work was supported by National Institutes of Health Grant CA77325 (to P. R.). 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.

These authors contributed equally to this work.

A fellow of the Leukemia and Lymphoma Society.

^¶ To whom correspondence should be addressed: The Scripps Research Institute, 10550 North Torrey Pines Rd., La Jolla, CA 92037. Tel.: 858-784-8273; Fax: 858-784-2265; E-mail: prussell{at}scripps.edu.

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