Imperial College London
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DrRobertMahen

Faculty of Natural Sciences, Department of Physics

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r.mahen

 
 
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Location

 

Blackett LaboratorySouth Kensington Campus

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Summary

 

Publications

Citation

BibTex format

@article{Bolderson:2012:10.1074/jbc.M112.368381,
author = {Bolderson, E and Savage, KI and Mahen, R and Pisupati, V and Graham, ME and Richard, DJ and Robinson, PJ and Venkitaraman, AR and Khanna, KK},
doi = {10.1074/jbc.M112.368381},
journal = {J Biol Chem},
pages = {28122--28131},
title = {Kruppel-associated Box (KRAB)-associated co-repressor (KAP-1) Ser-473 phosphorylation regulates heterochromatin protein 1β (HP1-β) mobilization and DNA repair in heterochromatin.},
url = {http://dx.doi.org/10.1074/jbc.M112.368381},
volume = {287},
year = {2012}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - The DNA damage response encompasses a complex series of signaling pathways that function to regulate and facilitate the repair of damaged DNA. Recent studies have shown that the repair of transcriptionally inactive chromatin, named heterochromatin, is dependent upon the phosphorylation of the co-repressor, Krüppel-associated box (KRAB) domain-associated protein (KAP-1), by the ataxia telangiectasia-mutated (ATM) kinase. Co-repressors, such as KAP-1, function to regulate the rigid structure of heterochromatin by recruiting histone-modifying enzymes, such HDAC1/2, SETDB1, and nucleosome-remodeling complexes such as CHD3. Here, we have characterized a phosphorylation site in the HP1-binding domain of KAP-1, Ser-473, which is phosphorylated by the cell cycle checkpoint kinase Chk2. Expression of a nonphosphorylatable S473A mutant conferred cellular sensitivity to DNA-damaging agents and led to defective repair of DNA double-strand breaks in heterochromatin. In addition, cells expressing S473A also displayed defective mobilization of the HP1-β chromodomain protein. The DNA repair defect observed in cells expressing S473A was alleviated by depletion of HP1-β, suggesting that phosphorylation of KAP-1 on Ser-473 promotes the mobilization of HP1-β from heterochromatin and subsequent DNA repair. These results suggest a novel mechanism of KAP-1-mediated chromatin restructuring via Chk2-regulated HP1-β exchange from heterochromatin, promoting DNA repair.
AU  - Bolderson,E
AU  - Savage,KI
AU  - Mahen,R
AU  - Pisupati,V
AU  - Graham,ME
AU  - Richard,DJ
AU  - Robinson,PJ
AU  - Venkitaraman,AR
AU  - Khanna,KK
DO  - 10.1074/jbc.M112.368381
EP  - 28131
PY  - 2012///
SP  - 28122
TI  - Kruppel-associated Box (KRAB)-associated co-repressor (KAP-1) Ser-473 phosphorylation regulates heterochromatin protein 1β (HP1-β) mobilization and DNA repair in heterochromatin.
T2  - J Biol Chem
UR  - http://dx.doi.org/10.1074/jbc.M112.368381
UR  - https://www.ncbi.nlm.nih.gov/pubmed/22715096
VL  - 287
ER  -
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