title: The human XPC DNA repair gene: arrangement, splice site information content and influence of a single nucleotide polymorphism in a splice acceptor site on alternative splicing and function.
abstract: XPC DNA repair gene mutations result in the cancer-prone disorder xeroderma pigmentosum. The XPC gene spans 33 kb and has 16 exons (82-882 bp) and 15 introns (0.08-5.4 kb). A 1.6 kb intron was found within exon 5. Sensitive real- time quantitative reverse transcription-polymerase chain reaction methods were developed to measure full-length XPC mRNA (the predominant form) and isoforms that skipped exons 4, 7 or 12. Exon 7 was skipped in approximately 0.07% of XPC mRNAs, consistent with the high information content of the exon 7 splice acceptor and donor sites (12.3 and 10.4 bits). In contrast, exon 4 was skipped in approximately 0.7% of the XPC mRNAs, consistent with the low information content of the exon 4 splice acceptor (-0.1 bits). A new common C/A single nucleotide polymorphism in the XPC intron 11 splice acceptor site (58% C in 97 normals) decreased its information content from 7.5 to 5.1 bits. Fibroblasts homozygous for A/A had significantly higher levels (approximately 2.6-fold) of the XPC mRNA isoform that skipped exon 12 than those homozygous for C/C. This abnormally spliced XPC mRNA isoform has diminished DNA repair function and may contribute to cancer susceptibility.
authors.affiliation: Basic Research Laboratory, National Cancer Institute, Building 37 Room 3E24, Bethesda, MD 20892, USA.
authors.forename: Sikandar G
authors.initials: SG
authors.lastname: Khan
authors.forename: Vanessa
authors.initials: V
authors.lastname: Muniz-Medina
authors.forename: Tala
authors.initials: T
authors.lastname: Shahlavi
authors.forename: Carl C
authors.initials: CC
authors.lastname: Baker
authors.forename: Hiroki
authors.initials: H
authors.lastname: Inui
authors.forename: Takahiro
authors.initials: T
authors.lastname: Ueda
authors.forename: Steffen
authors.initials: S
authors.lastname: Emmert
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Schneider
authors.forename: Kenneth H
authors.initials: KH
authors.lastname: Kraemer
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005347:Fibroblasts; D005787:Gene Frequency / Q000235:genetics; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007438:Introns / Q000235:genetics; D015810:Linkage Disequilibrium / Q000235:genetics; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000235:genetics; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D020033:Protein Isoforms / Q000235:genetics; D022821:RNA Splice Sites / Q000235:genetics*; D017384:Sequence Deletion
chemical_list: D004268:DNA-Binding Proteins; D020033:Protein Isoforms; D022821:RNA Splice Sites; C086984:XPC protein, human