期刊
DNA REPAIR
卷 35, 期 -, 页码 116-125出版社
ELSEVIER
DOI: 10.1016/j.dnarep.2015.10.002
关键词
FHA domain; DNA break repair; DNA-damage signalling
资金
- MRC [G0830]
- BBSRC [BB/F013930/1]
- Medical Research Council, UK [U117584228]
- Biotechnology and Biological Sciences Research Council [BB/F013930/1] Funding Source: researchfish
- Cancer Research UK [16771] Funding Source: researchfish
- Medical Research Council [1254166, MR/J006750/1, MC_U117584228, U117531954, MC_U117533887] Funding Source: researchfish
- The Francis Crick Institute [10156, 10029] Funding Source: researchfish
- BBSRC [BB/F013930/1] Funding Source: UKRI
- MRC [MC_U117533887, MR/J006750/1, MC_U117584228] Funding Source: UKRI
Aprataxin, aprataxin and PNKP-like factor (APLF) and polynucleotide kinase phosphatase (PNKP) are key DNA-repair proteins with diverse functions but which all contain a homologous forkhead-associated (FHA) domain. Their primary binding targets are casein kinase 2-phosphorylated forms of the XRCC1 and XRCC4 scaffold molecules which respectively coordinate single-stranded and double-stranded DNA break repair pathways. Here, we present the high-resolution X-ray structure of a complex of phosphorylated XRCC4 with APLF, the most divergent of the three FHA domain family members. This, combined with NMR and biochemical analysis of aprataxin and APLF binding to singly and multiply-phosphorylated forms of XRCC1 and XRCC4, and comparison with PNKP reveals a pattern of distinct but overlapping binding specificities that are differentially modulated by multi-site phosphorylation. Together, our data illuminate important differences between activities of the three phospho-binding domains, in spite of a close evolutionary relationship between them. (C) 2015 The Authors. Published by Elsevier B.V.
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