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CK2 phosphorylation-dependent interaction between aprataxin and MDC1 in the DNA damage response
Olivier J Becherel1, Burkhard Jakob, Amy L Cherry
1Queensland Institute of Medical Research, Radiation Biology and Oncology, Brisbane, QLD 4029, Australia.
Nucleic Acids Research
|December 17, 2009
Summary
Aprataxin, defective in ataxia oculomotor apraxia type 1, repairs DNA damage. It interacts with MDC1 at DNA damage sites, aiding in processing DNA breaks.
Area of Science:
- Molecular Biology
- Genetics
- Biochemistry
Background:
- Aprataxin is crucial for resolving DNA ligation intermediates in DNA repair.
- Defects in aprataxin cause the neurodegenerative disorder ataxia oculomotor apraxia type 1.
Purpose of the Study:
- To investigate the role of aprataxin in DNA damage response.
- To elucidate the interaction between aprataxin and mediator of DNA-damage checkpoint protein 1 (MDC1).
Main Methods:
- Localization studies at sites of DNA damage induced by high LET radiation.
- Co-immunoprecipitation assays to study protein interactions.
- X-ray crystallography and mutagenesis to analyze aprataxin FHA domain structure and binding.
- Modeling of protein-peptide interactions.
Main Results:
- Aprataxin localizes to DNA damage sites and binds to MDC1 via a phosphorylation-dependent interaction.
- The aprataxin FHA domain interacts with casein kinase 2 di-phosphorylated S-D-T-D motifs in MDC1.
- An unusual FHA binding mechanism involving basic residues was identified.
- Mutation of aprataxin Arg29 disrupted MDC1 interaction and recruitment to DNA damage sites.
Conclusions:
- Aprataxin participates in both single-strand break repair and the processing of certain double-strand breaks.
- The interaction with MDC1 is critical for aprataxin's recruitment to DNA damage sites.
- This study reveals a novel mechanism for aprataxin in DNA double-strand break repair.
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