Spatial organization of the mammalian genome surveillance machinery in response to DNA strand breaks.
Journal Article (Journal Article)
We show that DNA double-strand breaks (DSBs) induce complex subcompartmentalization of genome surveillance regulators. Chromatin marked by gamma-H2AX is occupied by ataxia telangiectasia-mutated (ATM) kinase, Mdc1, and 53BP1. In contrast, repair factors (Rad51, Rad52, BRCA2, and FANCD2), ATM and Rad-3-related (ATR) cascade (ATR, ATR interacting protein, and replication protein A), and the DNA clamp (Rad17 and -9) accumulate in subchromatin microcompartments delineated by single-stranded DNA (ssDNA). BRCA1 and the Mre11-Rad50-Nbs1 complex interact with both of these compartments. Importantly, some core DSB regulators do not form cytologically discernible foci. These are further subclassified to proteins that connect DSBs with the rest of the nucleus (Chk1 and -2), that assemble at unprocessed DSBs (DNA-PK/Ku70), and that exist on chromatin as preassembled complexes but become locally modified after DNA damage (Smc1/Smc3). Finally, checkpoint effectors such as p53 and Cdc25A do not accumulate at DSBs at all. We propose that subclassification of DSB regulators according to their residence sites provides a useful framework for understanding their involvement in diverse processes of genome surveillance.
Full Text
Duke Authors
Cited Authors
- Bekker-Jensen, S; Lukas, C; Kitagawa, R; Melander, F; Kastan, MB; Bartek, J; Lukas, J
Published Date
- April 24, 2006
Published In
Volume / Issue
- 173 / 2
Start / End Page
- 195 - 206
PubMed ID
- 16618811
Pubmed Central ID
- PMC2063811
International Standard Serial Number (ISSN)
- 0021-9525
Digital Object Identifier (DOI)
- 10.1083/jcb.200510130
Language
- eng
Conference Location
- United States