Multifactorial contributions to an acute DNA damage response by BRCA1/BARD1-containing complexes
- Roger A. Greenberg1,2,5,
- Bijan Sobhian1,2,5,
- Shailja Pathania1,2,
- Sharon B. Cantor4,
- Yoshihiro Nakatani3, and
- David M. Livingston1,2,6
- 1Department of Genetics, 2Department of Medicine, and 3Department of Biochemistry and Molecular Pharmacology, Harvard Medical School and The Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA; 4Department of Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA
Abstract
The BRCA1 gene product and its stoichiometric binding partner, BARD1, play a vital role in the cellular response to DNA damage. However, how they acquire specific biochemical functions after DNA damage is poorly understood. Following exposure to genotoxic stress, DNA damage-specific interactions were observed between BRCA1/BARD1 and the DNA damage-response proteins, TopBP1 and Mre11/Rad50/NBS1. Two distinct DNA damage-dependent super complexes emerged; their activation was dependent, in part, on the actions of specific checkpoint kinases, and each super complex contributed to a distinctive aspect of the DNA damage response. The results support a new, multifactorial model that describes how genotoxic stress enables BRCA1 to execute a diverse set of DNA damage-response functions.
Keywords
Footnotes
-
Supplemental material is available at http://www.genesdev.org.
-
Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/gad.1381306.
-
↵5 These authors contributed equally to this work.
-
↵6 Corresponding author.
↵6 E-MAIL david_livingston{at}dfci.harvard.edu; FAX (617) 632-4381.
-
- Accepted November 2, 2005.
- Received October 3, 2005.
- Cold Spring Harbor Laboratory Press
