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

Nucleic Acids Research
Mariangela SabatellaW Vermeulen

Abstract

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.

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Citations

Mar 29, 2019·Clinical Genetics·Debora FerriElena Botta
Sep 29, 2019·Nature Reviews. Molecular Cell Biology·Hannes LansJurgen A Marteijn
Dec 20, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Maryam FaridounniaRolf Boelens
May 27, 2020·Genetics and Molecular Biology·Alexandre Teixeira VessoniCamila Carrião Machado Garcia
Aug 9, 2019·Cellular and Molecular Life Sciences : CMLS·Mariangela SabatellaHannes Lans
Jan 14, 2021·Cell Reports·Mariangela SabatellaHannes Lans

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Methods Mentioned

BETA
FCS
fluorescence recovery after photobleaching
transfection

Software Mentioned

FIJI
LAS AF

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