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

Olivier J. Becherel; Burkhard Jakob; Amy L. Cherry; Nuri Gueven; Markus Fusser; Amanda W. Kijas; Cheng Peng; Sachin Katyal; Peter J. McKinnon; Junjie Chen; Bernd Epe; Stephen J. Smerdon; Gisela Taucher-Scholz; Martin F. Lavin

doi:10.1093/nar/gkp1149

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

Olivier J. Becherel, Burkhard Jakob, Amy L. Cherry, Nuri Gueven, Markus Fusser, Amanda W. Kijas, Cheng Peng, Sachin Katyal, Peter J. McKinnon, Junjie Chen, Bernd Epe, Stephen J. Smerdon, Gisela Taucher-Scholz, Martin F. Lavin

Experimental Radiation Oncology

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Abstract

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.

Original language	English (US)
Article number	gkp1149
Pages (from-to)	1489-1503
Number of pages	15
Journal	Nucleic acids research
Volume	38
Issue number	5
DOIs	https://doi.org/10.1093/nar/gkp1149
State	Published - Dec 14 2009

ASJC Scopus subject areas

Genetics

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Becherel, O. J., Jakob, B., Cherry, A. L., Gueven, N., Fusser, M., Kijas, A. W., Peng, C., Katyal, S., McKinnon, P. J., Chen, J., Epe, B., Smerdon, S. J., Taucher-Scholz, G., & Lavin, M. F. (2009). CK2 phosphorylation-dependent interaction between aprataxin and MDC1 in the DNA damage response. Nucleic acids research, 38(5), 1489-1503. Article gkp1149. https://doi.org/10.1093/nar/gkp1149

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abstract = "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.",

author = "Becherel, {Olivier J.} and Burkhard Jakob and Cherry, {Amy L.} and Nuri Gueven and Markus Fusser and Kijas, {Amanda W.} and Cheng Peng and Sachin Katyal and McKinnon, {Peter J.} and Junjie Chen and Bernd Epe and Smerdon, {Stephen J.} and Gisela Taucher-Scholz and Lavin, {Martin F.}",

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doi = "10.1093/nar/gkp1149",

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AU - Becherel, Olivier J.

AU - Jakob, Burkhard

AU - Cherry, Amy L.

AU - Gueven, Nuri

AU - Fusser, Markus

AU - Kijas, Amanda W.

AU - Peng, Cheng

AU - Katyal, Sachin

AU - McKinnon, Peter J.

AU - Chen, Junjie

AU - Epe, Bernd

AU - Smerdon, Stephen J.

AU - Taucher-Scholz, Gisela

AU - Lavin, Martin F.

PY - 2009/12/14

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N2 - 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.

AB - 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.

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

Abstract

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