title: A Drosophila XPD model links cell cycle coordination with neuro-development and suggests links to cancer.
abstract: XPD functions in transcription, DNA repair and in cell cycle control. Mutations in human XPD (also known as ERCC2) mainly cause three clinical phenotypes: xeroderma pigmentosum (XP), Cockayne syndrome (XP/CS) and trichothiodystrophy (TTD), and only XP patients have a high predisposition to developing cancer. Hence, we developed a fly model to obtain novel insights into the defects caused by individual hypomorphic alleles identified in human XP-D patients. This model revealed that the mutations that displayed the greatest in vivo UV sensitivity in Drosophila did not correlate with those that led to tumor formation in humans. Immunoprecipitations followed by targeted quantitative MS/MS analysis showed how different xpd mutations affected the formation or stability of different transcription factor IIH (TFIIH) subcomplexes. The XP mutants most clearly linked to high cancer risk, Xpd R683W and R601L, showed a reduced interaction with the core TFIIH and also an abnormal interaction with the Cdk-activating kinase (CAK) complex. Interestingly, these two XP alleles additionally displayed high levels of chromatin loss and free centrosomes during the rapid nuclear division phase of the Drosophila embryo. Finally, the xpd mutations showing defects in the coordination of cell cycle timing during the Drosophila embryonic divisions correlated with those human mutations that cause the neurodevelopmental abnormalities and developmental growth defects observed in XP/CS and TTD patients.
authors.affiliation: Institute of Cell Biology, University of Bern, 3012 Bern, Switzerland.
authors.forename: Karin
authors.initials: K
authors.lastname: Stettler
authors.affiliation: Institute of Cell Biology, University of Bern, 3012 Bern, Switzerland.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Biology, Philipps-University Marburg, 35032 Marburg, Germany.
authors.forename: Björn
authors.initials: B
authors.lastname: Sandrock
authors.affiliation: Department of Clinical Research, University of Bern, 3010 Bern, Switzerland.
authors.forename: Sophie
authors.initials: S
authors.lastname: Braga-Lagache
authors.affiliation: Department of Clinical Research, University of Bern, 3010 Bern, Switzerland.
authors.forename: Manfred
authors.initials: M
authors.lastname: Heller
authors.affiliation: Institute of Mathematical Statistics and Actuarial Science, University of Bern, 3012 Bern, Switzerland.
authors.forename: Lutz
authors.initials: L
authors.lastname: Dümbgen
authors.affiliation: Institute of Cell Biology, University of Bern, 3012 Bern, Switzerland. beat.suter@izb.unibe.ch.
authors.forename: Beat
authors.initials: B
authors.lastname: Suter
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D002453:Cell Cycle; D002843:Chromatin / Q000378:metabolism; D003001:Cloning, Molecular; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000378:metabolism; D004331:Drosophila melanogaster / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D009369:Neoplasms / Q000378:metabolism*; D009474:Neurons / Q000473:pathology; D010641:Phenotype; D012307:Risk Factors; D017386:Sequence Homology, Amino Acid; D051758:Transcription Factor TFIIH / Q000378:metabolism; D014983:Xeroderma Pigmentosum / Q000235:genetics*; D000095043:Cyclin-Dependent Kinase-Activating Kinase
chemical_list: D002843:Chromatin; D029721:Drosophila Proteins; C520555:mrn protein, Drosophila; D051758:Transcription Factor TFIIH; D018844:Cyclin-Dependent Kinases; D000095043:Cyclin-Dependent Kinase-Activating Kinase
keywords: Cell cycle synchronization; Mitotic defect; Xeroderma pigmentosum; Xpd