Nucleic Acids Research Advance Access originally published online on August 8, 2007
Nucleic Acids Research 2007 35(16):5312-5322; doi:10.1093/nar/gkm493
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Nucleic Acids Research, 2007, Vol. 35, No. 16 5312-5322
© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Molecular Biology |
Phospho-epitope binding by the BRCT domains of hPTIP controls multiple aspects of the cellular response to DNA damage
MRC Protein Phosphorylation Unit, Sir James Black Centre, University of Dundee, Dundee DD1 5EH, Scotland, UK
*To whom correspondence should be addressed. Tel: +44 1382 385490; Fax: +44 1382 223778; Email: j.rouse{at}dundee.ac.uk
Received April 13, 2007. Revised May 17, 2007. Accepted June 6, 2007.
Human (h)PTIP plays important but poorly understood roles in cellular responses to DNA damage. hPTIP interacts with 53BP1 tumour suppressor but only when 53BP1 is phosphorylated by ATM after DNA damage although the mechanism(s) and significance of the interaction of these two proteins are unclear. Here, we pinpoint a single ATM-phosphorylated residue in 53BP1—Ser25—that is required for binding of 53BP1 to hPTIP. Binding of phospho-Ser25 to hPTIP in vitro and in vivo requires two closely apposed pairs of BRCT domains at the C-terminus of hPTIP and neither pair alone can bind to phospho-Ser25, even though one of these BRCT pairs in isolation can bind to other ATM-phosphorylated epitopes. Mutations in 53BP1 and in hPTIP that prevent the interaction of the two proteins, render cells hypersensitive to DNA damage and weaken ATM signalling. The C-terminal BRCT domains of hPTIP are also required for stable retention of hPTIP at sites of DNA damage but this appears to be independent of binding to 53BP1. Thus, the BRCT domains of hPTIP play important roles in the cellular response to DNA damage.
Present address: Paul A. Jowsey, Clinical and Laboratory Sciences, University of Newcastle, Newcastle Upon Tyne NE1 7RU England.
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