Both XPD alleles contribute to the phenotype of compound heterozygote xeroderma pigmentosum patients.

The Journal of Experimental Medicine
Takahiro UedaJean-Marc Egly

Abstract

Mutations in the XPD subunit of the DNA repair/transcription factor TFIIH result in the rare recessive genetic disorder xeroderma pigmentosum (XP). Many XP patients are compound heterozygotes with a "causative" XPD point mutation R683W and different second mutant alleles, considered "null alleles." However, there is marked clinical heterogeneity (including presence or absence of skin cancers or neurological degeneration) in these XPD/R683W patients, thus suggesting a contribution of the second allele. Here, we report XP patients carrying XPD/R683W and a second XPD allele either XPD/Q452X, /I455del, or /199insPP. We performed a systematic study of the effect of these XPD mutations on several enzymatic functions of TFIIH and found that each mutation exhibited unique biochemical properties. Although all the mutations inhibited the nucleotide excision repair (NER) by disturbing the XPD helicase function, each of them disrupted specific molecular steps during transcription: XPD/Q452X hindered the transactivation process, XPD/I455del disturbed RNA polymerase II phosphorylation, and XPD/199insPP inhibited kinase activity of the cdk7 subunit of TFIIH. The broad range and severity of clinical features in XP patients arise from a broad s...Continue Reading

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Citations

Dec 13, 2012·European Journal of Human Genetics : EJHG·Xiaolong ZhouKenneth H Kraemer
May 11, 2012·Nature Reviews. Molecular Cell Biology·Emmanuel Compe, Jean-Marc Egly
Feb 6, 2013·Proceedings of the National Academy of Sciences of the United States of America·Wassim AbdulrahmanArnaud Poterszman
Jan 2, 2013·Mutation Research·Avvaru N Suhasini, Robert M Brosh
Oct 11, 2012·DNA Repair·Marieke van de VenJames R Mitchell
Oct 1, 2011·Ophthalmology·Brian P BrooksKenneth H Kraemer
Feb 18, 2016·Proceedings of the National Academy of Sciences of the United States of America·Hiva FassihiAlan R Lehmann
Jun 15, 2016·Annual Review of Biochemistry·Emmanuel Compe, Jean-Marc Egly
Jun 6, 2016·DNA Repair·Bennett Van HoutenCaroline Kisker
Oct 24, 2014·PLoS Genetics·Hussein TraboulsiEmmanuel Compe
Apr 3, 2020·Journal of the European Academy of Dermatology and Venereology : JEADV·K M SantiagoM I Achatz
May 22, 2019·Nature Structural & Molecular Biology·Chunli YanIvaylo Ivanov
Jul 8, 2018·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Qiang LiKent W Mouw
Jun 22, 2021·Annual Review of Biochemistry·Emmanuel Compe, Jean-Marc Egly
Jul 25, 2012·Trends in Genetics : TIG·Irene KamileriGeorge A Garinis

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Methods Mentioned

BETA
transfection
PCR
ChIP
immunoprecipitation
in vitro transcription
footprinting
FCS
electrophoresis
gel filtration

Software Mentioned

Genetool

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