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Molecular and Cellular Biology, May 2001, p. 3445-3450, Vol. 21, No. 10
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.10.3445-3450.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Involvement of Brca1 in S-Phase and G2-Phase Checkpoints after Ionizing Irradiation

Bo Xu, Seong-tae Kim, and Michael B. Kastan*

Department of Hematology-Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105

Received 16 January 2001/Returned for modification 13 February 2001/Accepted 18 February 2001

Cell cycle arrests in the G1, S, and G2 phases occur in mammalian cells after ionizing irradiation and appear to protect cells from permanent genetic damage and transformation. Though Brca1 clearly participates in cellular responses to ionizing radiation (IR), conflicting conclusions have been drawn about whether Brca1 plays a direct role in cell cycle checkpoints. Normal Nbs1 function is required for the IR-induced S-phase checkpoint, but whether Nbs1 has a definitive role in the G2/M checkpoint has not been established. Here we show that Atm and Brca1 are required for both the S-phase and G2 arrests induced by ionizing irradiation while Nbs1 is required only for the S-phase arrest. We also found that mutation of serine 1423 in Brca1, a target for phosphorylation by Atm, abolished the ability of Brca1 to mediate the G2/M checkpoint but did not affect its S-phase function. These results clarify the checkpoint roles for each of these three gene products, demonstrate that control of cell cycle arrests must now be included among the important functions of Brca1 in cellular responses to DNA damage, and suggest that Atm phosphorylation of Brca1 is required for the G2/M checkpoint.

* Corresponding author. Mailing address: Department of Hematology-Oncology, St. Jude Children's Research Hospital, 332 N. Lauderdale St., Memphis, TN 38105. Phone: (901) 495-3968. Fax: (901) 495-3966. E-mail: Michael.Kastan{at}stjude.org.

Molecular and Cellular Biology, May 2001, p. 3445-3450, Vol. 21, No. 10
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.10.3445-3450.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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