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Efficient single-strand break repair requires binding to both poly(ADP-ribose) and DNA by the central BRCT domain of XRCC1

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posted on 2023-06-09, 16:35 authored by Luis M Polo, Yingqi Xu, Peter Hornyak, Fernando Garces, Zhihong Zeng, Richard Hailstone, Steve J Matthews, Keith CaldecottKeith Caldecott, Antony OliverAntony Oliver, Laurence PearlLaurence Pearl
XRCC1 accelerates repair of DNA single-strand breaks by acting as a scaffold protein for the recruitment of Pol-beta, LigIII-alpha and end-processing factors such as PNKP and APTX. XRCC1 itself is recruited to DNA damage through interaction of its central BRCT domain with poly-(ADP-ribose) chains generated by PARP1 or PARP2. XRCC1 is believed to interact directly with DNA at sites of damage, but the molecular basis for this interaction within XRCC1 remains unclear. We now show that the central BRCT domain simultaneously mediates interaction of XRCC1 with poly-(ADP-ribose) and DNA, through separate and non-overlapping binding sites on opposite faces of the domain. Mutation of residues within the DNA binding site, which includes the site of a common disease-associated human polymorphism, affects DNA binding of this XRCC1 domain in vitro, and impairs XRCC1 recruitment and retention at DNA damage and repair of single-strand breaks in vivo.

Funding

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

Structural Biology of DNA Damage Response and Repair Mechanisms and its Exploitation for Drug Discov; G0891; CANCER RESEARCH UK; C302/A14532

Structural Biology of DNA Damage Response and Repair Mechanisms; G2176; CANCER RESEARCH UK; C302/A24386

History

Publication status

  • Published

File Version

  • Published version

Journal

Cell Reports

ISSN

2211-1247

Publisher

Elsevier

Issue

3

Volume

26

Page range

573-581.e5

Department affiliated with

  • Sussex Centre for Genome Damage Stability Publications

Research groups affiliated with

  • Genome Damage and Stability Centre Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2019-02-05

First Open Access (FOA) Date

2019-02-05

First Compliant Deposit (FCD) Date

2019-02-05

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