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XRCC1 protects transcription from toxic PARP1 activity during DNA base excision repair

Marek Adamowicz1, Richard Hailstone1, Annie A Demin1

  • 1Genome Damage and Stability Centre and Sussex Drug Discovery Centre, School of Life Sciences, University of Sussex, Brighton, UK.

Nature Cell Biology
|November 23, 2021
PubMed

Insights

Genetic defects in DNA repair cause neurological disease via toxic PARP1 activity. XRCC1 loss impairs transcriptional recovery by increasing PARP1 and USP3 activity, offering therapeutic targets.

Area of Science:

  • Molecular Biology
  • Genetics
  • Neuroscience

Background:

  • Genetic defects in DNA single-strand break (SSB) repair are linked to neurological diseases.
  • Toxic activity of the PARP1 protein is implicated, but mechanisms remain unclear.

Purpose of the Study:

  • To elucidate the mechanism by which toxic PARP1 activity triggers cellular dysfunction in DNA repair-deficient states.
  • To investigate the role of XRCC1 in regulating PARP1 activity and its impact on transcriptional recovery.

Main Methods:

  • Utilized human cell lines lacking XRCC1, patient-derived fibroblasts with XRCC1 mutations, and Xrcc1-/- mouse neurons.
  • Assessed transcriptional recovery following DNA base damage.
  • Investigated the recruitment and activity of PARP1 and USP3.
  • Examined histone ubiquitination levels.

Main Results:

  • Cells lacking XRCC1 exhibit delayed transcriptional recovery after DNA base damage.
  • This defect is attributed to excessive PARP1 activity during base excision repair due to loss of XRCC1 regulation.
  • Aberrant PARP1 activity promotes USP3 recruitment and activity, reducing essential monoubiquitinated histones.
  • Inhibition or deletion of PARP1 or USP3 restored transcriptional recovery in XRCC1-deficient cells.

Conclusions:

  • XRCC1 is crucial for regulating PARP1 activity during DNA repair.
  • Dysregulated PARP1 and USP3 contribute to transcriptional impairment in XRCC1 deficiency.
  • PARP1 and USP3 represent potential therapeutic targets for neurological diseases associated with DNA repair defects.

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