XPC Branch-Point Sequence Mutations Disrupt U2 snRNP Binding, Resulting in Abnormal pre-mRNA Splicing in Xeroderma Pigmentosum Patients

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dc.authoridZheng, Zhi-Ming/0000-0001-5547-7912
dc.authoridKHAN, SIKANDAR/0000-0001-9957-4132
dc.authoridKraemer, Kenneth/0000-0002-2689-3316
dc.authorwosidMetin, Ahmet/ABB-7187-2020
dc.authorwosidZheng, Zhi-Ming/L-6383-2019
dc.authorwosidMetin, Ahmet/HJY-7499-2023
dc.contributor.authorKhan, Sikandar G.
dc.contributor.authorYamanegi, Koji
dc.contributor.authorZheng, Zhi-Ming
dc.contributor.authorBoyle, Jennifer
dc.contributor.authorImoto, Kyoko
dc.contributor.authorOh, Kyu-Seon
dc.contributor.authorBaker, Carl C.
dc.date.accessioned2024-08-04T20:32:15Z
dc.date.available2024-08-04T20:32:15Z
dc.date.issued2010
dc.departmentİnönü Üniversitesien_US
dc.description.abstractMutations in two branch-point sequences (BPS) in intron 3 of the XPC DNA repair gene affect pre-mRNA splicing in association with xeroderma pigmentosum (XP) with many skin cancers (X-P101TMA) or no skin cancer (XT72TMA), respectively. To investigate the mechanism of these abnormalities we now report that transfection of minigenes with these mutations revealed abnormal XPC pre-mRNA splicing that mimicked pre-mRNA splicing in the patients' cells. DNA oligonucleotide-directed RNase H digestion demonstrated that mutations in these BPS disrupt U2 snRNP-BPS interaction. XP101TMA cells had no detectable XTC protein but XT72TMA had 29% of normal levels. A small amount of XTC protein was detected at sites of localized ultraviolet (UV),damaged DNA in XT72TMA cells which then recruited other nucleotide excision repair (NER) proteins. In contrast, XP101TMA cells had no detectable recruitment of XTC or other NER proteins. Post-UV survival and photoproduct assays revealed greater reduction in DNA repair in XP101TMA cells than in XT72TMA. Thus mutations in XPC BPS resulted in disruption of U2 snRNPBPS interaction leading to abnormal pre-mRNA splicing and reduced XPC protein. At the cellular level these changes were associated with features of reduced DNA repair including diminished NER protein recruitment reduced post-UV survival and impaired photoproduct removal. Hum Mutat 31:167-175, 2010. Published 2009 Wiley-Liss, Inc.en_US
dc.description.sponsorshipNIH; Center for Cancer Research of the National Cancel Instituteen_US
dc.description.sponsorshipThe research was supported by the Intramural Research Program of the NIH and the Center for Cancer Research of the National Cancel Institute. We thank Dr. Susan Garfield of the CCR Confocal Microscopy Core Facility for assistance with the confocal microscopy and Ms. Najealicka Armstrong for assistance with the photoproduct assay.en_US
dc.identifier.doi10.1002/humu.21166
dc.identifier.endpage175en_US
dc.identifier.issn1059-7794
dc.identifier.issn1098-1004
dc.identifier.issue2en_US
dc.identifier.pmid19953607en_US
dc.identifier.scopus2-s2.0-75149191448en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.startpage167en_US
dc.identifier.urihttps://doi.org/10.1002/humu.21166
dc.identifier.urihttps://hdl.handle.net/11616/94961
dc.identifier.volume31en_US
dc.identifier.wosWOS:000274461800007en_US
dc.identifier.wosqualityQ1en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherWileyen_US
dc.relation.ispartofHuman Mutationen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subjectXPCen_US
dc.subjectDNA repairen_US
dc.subjectpre-mRNA splicingen_US
dc.subjectxeroderma pigmentosumen_US
dc.subjectskin canceren_US
dc.subjectU2 snRNPen_US
dc.titleXPC Branch-Point Sequence Mutations Disrupt U2 snRNP Binding, Resulting in Abnormal pre-mRNA Splicing in Xeroderma Pigmentosum Patientsen_US
dc.typeArticleen_US

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