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A disease-associated XPA allele interferes with TFIIH binding and primarily affects transcription-coupled nucleotide excision repair

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Title
A disease-associated XPA allele interferes with TFIIH binding and primarily affects transcription-coupled nucleotide excision repair
Author(s)
van, den Heuvel D.; Mihyun Kim; Wondergem, A.P.; van, der Meer P.J.; Witkamp, M.; Lambregtse, F.; Hyun-Suk Kim; Kan, F.; Apelt, K.; Kragten, A.; González-Prieto, R.; Vertegaal, A.C.O.; Jung-Eun Yeo; Byung-Gyu Kim; van, Doorn R.; Orlando D. Schärer; Luijsterburg, M.S.
Publication Date
2023-03
Journal
Proceedings of the National Academy of Sciences of the United States of America, v.120, no.11
Publisher
National Academy of Sciences
Abstract
XPA is a central scaffold protein that coordinates the assembly of repair complexes in the global genome (GG-NER) and transcription-coupled nucleotide excision repair (TC-NER) subpathways. Inactivating mutations in XPA cause xeroderma pigmentosum (XP), which is characterized by extreme UV sensitivity and a highly elevated skin cancer risk. Here, we describe two Dutch siblings in their late forties carrying a homozygous H244R substitution in the C-terminus of XPA. They present with mild cutaneous manifestations of XP without skin cancer but suffer from marked neurological features, including cerebellar ataxia. We show that the mutant XPA protein has a severely weakened interaction with the transcription factor IIH (TFIIH) complex leading to an impaired association of the mutant XPA and the downstream endonuclease ERCC1-XPF with NER complexes. Despite these defects, the patient-derived fibroblasts and reconstituted knockout cells carrying the XPAH244R substitution show intermediate UV sensitivity and considerable levels of residual GG-NER (∼50%), in line with the intrinsic properties and activities of the purified protein. By contrast, XPA-H244R cells are exquisitely sensitive to transcription- blocking DNA damage, show no detectable recovery of transcription after UV irradiation, and display a severe deficiency in TC-NER-associated unscheduled DNA synthesis. Our characterization of a new case of XPA deficiency that interferes with TFIIH binding and primarily affects the transcription-coupled subpathway of nucleotide excision repair, provides an explanation of the dominant neurological features in these patients, and reveals a specific role for the C-terminus of XPA in TC-NER. © 2023 the Author(s).
URI
https://pr.ibs.re.kr/handle/8788114/13389
DOI
10.1073/pnas.2208860120
ISSN
0027-8424
Appears in Collections:
Center for Genomic Integrity(유전체 항상성 연구단) > 1. Journal Papers (저널논문)
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