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Versatility in phospho-dependent molecular recognition of the XRCC1 and XRCC4 DNA-damage scaffolds by aprataxin-family FHA domains

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posted on 2023-06-09, 00:49 authored by Amy L Cherry, Timothy J Nott, Geoffrey Kelly, Stuart L Rulten, Keith CaldecottKeith Caldecott, Stephen J Smerdon
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.

Funding

Chromosomal Single-strand break Repair: Mechanisms & Degenerative Disease; G0830; MRC-MEDICAL RESEARCH COUNCIL; MR/J006750/1

History

Publication status

  • Published

File Version

  • Published version

Journal

DNA repair

ISSN

1568-7856

Publisher

Elsevier

Volume

35

Page range

116-125

Department affiliated with

  • Sussex Centre for Genome Damage Stability Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2016-04-11

First Open Access (FOA) Date

2016-04-11

First Compliant Deposit (FCD) Date

2016-04-11

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