Repair protein persistence at DNA lesions characterizes XPF defect with Cockayne syndrome features

Nucleic Acids Res. 2018 Oct 12;46(18):9563-9577. doi: 10.1093/nar/gky774.


The structure-specific ERCC1-XPF endonuclease plays a key role in DNA damage excision by nucleotide excision repair (NER) and interstrand crosslink repair. Mutations in this complex can either cause xeroderma pigmentosum (XP) or XP combined with Cockayne syndrome (XPCS-complex) or Fanconi anemia. However, most patients carry compound heterozygous mutations, which confounds the dissection of the phenotypic consequences for each of the identified XPF alleles. Here, we analyzed the functional impact of individual pathogenic XPF alleles on NER. We show that XP-causing mutations diminish XPF recruitment to DNA damage and only mildly affect global genome NER. In contrast, an XPCS-complex-specific mutation causes persistent recruitment of XPF and the upstream core NER machinery to DNA damage and severely impairs both global genome and transcription-coupled NER. Remarkably, persistence of NER factors at DNA damage appears to be a common feature of XPCS-complex cells, suggesting that this could be a determining factor contributing to the development of additional developmental and/or neurodegenerative features in XP patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Cell Line
  • Cockayne Syndrome / genetics*
  • Cockayne Syndrome / pathology
  • DNA Damage / genetics
  • DNA Repair / genetics
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / genetics*
  • Endonucleases / chemistry
  • Endonucleases / genetics*
  • Fanconi Anemia / genetics
  • Fanconi Anemia / pathology
  • Genome, Human / genetics
  • Humans
  • Multiprotein Complexes / chemistry
  • Multiprotein Complexes / genetics
  • Mutation / genetics
  • Protein Multimerization / genetics
  • Xeroderma Pigmentosum / genetics*


  • DNA-Binding Proteins
  • Multiprotein Complexes
  • xeroderma pigmentosum group F protein
  • ERCC1 protein, human
  • Endonucleases