CK2 phosphorylation-dependent interaction between aprataxin and MDC1 in the DNA damage response.
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.
Becherel
Olivier J
OJ
Queensland Institute of Medical Research, Radiation Biology and Oncology, Brisbane, QLD 4029, Australia.
Jakob
Burkhard
B
Cherry
Amy L
AL
Gueven
Nuri
N
Fusser
Markus
M
Kijas
Amanda W
AW
Peng
Cheng
C
Katyal
Sachin
S
McKinnon
Peter J
PJ
Chen
Junjie
J
Epe
Bernd
B
Smerdon
Stephen J
SJ
Taucher-Scholz
Gisela
G
Lavin
Martin F
MF
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D047390:Casein Kinase II / Q000378:metabolism*; D018797:Cell Cycle Proteins; D002460:Cell Line; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D018499:Linear Energy Transfer; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D054730:Protein Interaction Domains and Motifs; D015534:Trans-Activators / Q000378:metabolism
C438188:APTX protein, human; D048868:Adaptor Proteins, Signal Transducing; C514665:Aptx protein, mouse; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; C413163:MDC1 protein, human; C508937:MDC1 protein, mouse; D009687:Nuclear Proteins; D015534:Trans-Activators; D047390:Casein Kinase II