Two essential splice lariat branchpoint sequences in one intron in a xeroderma pigmentosum DNA repair gene

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dc.authoridKHAN, SIKANDAR/0000-0001-9957-4132
dc.authoridSchneider, Thomas/0000-0002-9841-1531
dc.authoridKraemer, Kenneth/0000-0002-2689-3316
dc.authorwosidMetin, Ahmet/HJY-7499-2023
dc.authorwosidMetin, Ahmet/ABB-7187-2020
dc.contributor.authorKhan, SG
dc.contributor.authorMetin, A
dc.contributor.authorGozukara, E
dc.contributor.authorInui, H
dc.contributor.authorShahlavi, T
dc.contributor.authorMuniz-Medina, V
dc.contributor.authorBaker, CC
dc.date.accessioned2024-08-04T20:13:39Z
dc.date.available2024-08-04T20:13:39Z
dc.date.issued2004
dc.departmentİnönü Üniversitesien_US
dc.description.abstractThe lariat branch point sequence (BPS) is crucial for splicing of human nuclear pre-mRNA yet BPS mutations have infrequently been reported to cause human disease. Using an inverse RT-PCR technique we mapped two BPS to the adenosine residues at positions -4 and -24 in intron 3 of the human XPC DNA repair gene. We identified homozygous mutations in each of these BPS in two newly diagnosed Turkish families with the autosomal recessive disorder xeroderma pigmentosum (XP). Cells from two severely affected children in family A harbor a homozygous point mutation in XPC intron 3 (-9 T to A), located within the downstream BPS. Using a real-time quantitative reverse transcriptase-polymerase chain reaction (QRT-PCR) assay, these cells expressed no detectable (<0.1%) normal XPC message. Instead they expressed an XPC mRNA isoform with deletion of exon 4 that has no DNA repair activity in a host cell reactivation (HCR) assay. In contrast, in cells from three mildly affected siblings in family B, the BPS adenosine located at the -24 position in XPC intron 3 is mutated to a G. Real-time QRT-PCR revealed 3-5% of normal XPC message. These cells from family B had a higher level of HCR than cells from the severely affected siblings in family A, who had multiple skin cancers. Mutations identified in two BPS of the XPC intron 3 resulted in alternative splicing that impaired DNA repair function, thus implicating both of these BPS as essential for normal pre-mRNA splicing. However, a small amount of normal XPC mRNA can provide partial protection against skin cancers.en_US
dc.description.sponsorshipIntramural NIH HHS [Z01 BC004517-31] Funding Source: Medlineen_US
dc.identifier.doi10.1093/hmg/ddh026
dc.identifier.endpage352en_US
dc.identifier.issn0964-6906
dc.identifier.issn1460-2083
dc.identifier.issue3en_US
dc.identifier.pmid14662655en_US
dc.identifier.scopus2-s2.0-10744223717en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.startpage343en_US
dc.identifier.urihttps://doi.org/10.1093/hmg/ddh026
dc.identifier.urihttps://hdl.handle.net/11616/93765
dc.identifier.volume13en_US
dc.identifier.wosWOS:000188795000009en_US
dc.identifier.wosqualityQ1en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherOxford Univ Pressen_US
dc.relation.ispartofHuman Molecular Geneticsen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subjectGroup-Cen_US
dc.subjectPolypyrimidine Tracten_US
dc.subjectInformation-Contenten_US
dc.subjectTranscript Levelsen_US
dc.subjectSite Mutationsen_US
dc.subjectSkin-Canceren_US
dc.subjectFamiliesen_US
dc.subjectDiseaseen_US
dc.subjectDisorderen_US
dc.subjectDeletionen_US
dc.titleTwo essential splice lariat branchpoint sequences in one intron in a xeroderma pigmentosum DNA repair geneen_US
dc.typeArticleen_US

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