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Nucleic Acids Research, 2002, Vol. 30, No. 22 4815-4822
© 2002 Oxford University Press

Functional analysis of FHA and BRCT domains of NBS1 in chromatin association and DNA damage responses

Song Zhao, William Renthal and Eva Y.-H. P. Lee*

Department of Molecular Medicine/Institute of Biotechnology, University of Texas Health Science Center, San Antonio, TX 78245, USA

*To whom correspondence should be addressed at present address: Department of Biological Chemistry and Department of Developmental and Cell Biology, University of California–Irvine, Sprague Hall, Room 122, 839 Medical Science Court, Irvine, CA 92697, USA. Tel: +1 949 824 9766; Fax: +1 949 824 9767; Email: elee{at}uci.edu
Present address: William Renthal, Department of Chemistry and Biochemistry, The University of Texas, Austin, TX 78712, USA

Rad50/Mre11/NBS1 (R/M/N) is a multi-functional protein complex involved in DNA repair, cell cycle checkpoint activation, DNA replication and replication block-induced responses. Ionizing radiation (IR) induces the phosphorylation of NBS1 and nuclear foci formation of the complex. Although it has been suggested that the R/M/N complex is associated with DNA damage sites, we present here biochemical evidence for chromatin association of the complex. We show that the chromatin association of R/M/N is independent of IR and ataxia telangiectasia mutated (ATM). We also demonstrate that optimal chromatin association of the Rad50/Mre11/NBS1 proteins requires both the conserved forkhead-associated (FHA) and breast cancer C-terminus (BRCT) domains of NBS1. Moreover, both these domains of NBS1 are required for its phosphorylation on Ser343 but not on Ser278. Importantly, both the FHA and BRCT domains are essential for IR-induced foci (IRIF) formation of R/M/N and S phase checkpoint activation, but only the BRCT domain is needed for cell survival after IR. These data demonstrate that the FHA and BRCT domains of NBS1 are crucial for the functions of the R/M/N complex.


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