CK2 phosphorylation-dependent interaction between aprataxin and MDC1 in the DNA damage response

被引：51

作者：

Becherel, Olivier J. ^{[1
]}

Jakob, Burkhard ^{[2
]}

Cherry, Amy L. ^{[3
]}

Gueven, Nuri ^{[1
]}

Fusser, Markus ^{[4
]}

Kijas, Amanda W. ^{[1
]}

Peng, Cheng ^{[1
]}

Katyal, Sachin ^{[5
]}

McKinnon, Peter J. ^{[5
]}

Chen, Junjie ^{[6
]}

Epe, Bernd ^{[4
]}

Smerdon, Stephen J. ^{[3
]}

Taucher-Scholz, Gisela ^{[2
]}

Lavin, Martin F. ^{[1
,7
]}

机构：

[1] Queensland Inst Med Res Radiat Biol & Oncol, Brisbane, Qld 4029, Australia

[2] GSI Helmholtzzentrum Schwerionenforsch GmBH, D-64291 Darmstadt, Germany

[3] Natl Inst Med Res, MRC, London NW7 1AA, England

[4] Johannes Gutenberg Univ Mainz, Inst Pharm, D-6500 Mainz, Germany

[5] St Jude Childrens Hosp, Dept Genet & Tumor Cell Biol, Memphis, TN 38105 USA

[6] Univ Texas MD Anderson Canc Ctr, Dept Expt Radiat Oncol, Houston, TX 77030 USA

[7] Univ Queensland, Cent Clin Div, Brisbane, Qld, Australia

来源：

NUCLEIC ACIDS RESEARCH | 2010年 / 38卷 / 05期

基金：

英国医学研究理事会;

关键词：

STRAND-BREAK REPAIR; HISTIDINE TRIAD SUPERFAMILY; OCULAR MOTOR APRAXIA; HISTONE H2AX; FHA DOMAIN; ATAXIA-TELANGIECTASIA; POLYNUCLEOTIDE KINASE; CHROMATIN RETENTION; CELLULAR-RESPONSES; PROTEIN APRATAXIN;

D O I：

10.1093/nar/gkp1149

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Aprataxin, defective in the neurodegenerative disorder ataxia oculomotor apraxia type 1, resolves abortive DNA ligation intermediates during DNA repair. Here, we demonstrate that aprataxin localizes at sites of DNA damage induced by high LET radiation and binds to mediator of DNA-damage checkpoint protein 1 (MDC1/NFBD1) through a phosphorylation-dependent interaction. This interaction is mediated via the aprataxin FHA domain and multiple casein kinase 2 di-phosphorylated S-D-T-D motifs in MDC1. X-ray structural and mutagenic analysis of aprataxin FHA domain, combined with modelling of the pSDpTD peptide interaction suggest an unusual FHA binding mechanism mediated by a cluster of basic residues at and around the canonical pT-docking site. Mutation of aprataxin FHA Arg29 prevented its interaction with MDC1 and recruitment to sites of DNA damage. These results indicate that aprataxin is involved not only in single strand break repair but also in the processing of a subset of double strand breaks presumably through its interaction with MDC1.

引用

页码：1489 / 1503

页数：15

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