A Drosophila XPD model links cell cycle coordination with neuro-development and suggests links to cancer

Stettler, Karin; Li, Xiaoming; Sandrock, Björn; Braga, Sophie Marie-Pierre; Heller, Manfred; Dümbgen, Lutz; Suter, Beat (2015). A Drosophila XPD model links cell cycle coordination with neuro-development and suggests links to cancer. Disease models & mechanisms, 8(1), pp. 81-91. Company of Biologists Ltd. 10.1242/dmm.016907

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DCR Services > Core Facility Massenspektrometrie- und Proteomics-Labor
08 Faculty of Science > Department of Biology > Institute of Cell Biology
08 Faculty of Science > Department of Mathematics and Statistics > Institute of Mathematical Statistics and Actuarial Science

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Stettler, Karin; Li, Xiaoming; Braga, Sophie Marie-Pierre; Heller, Manfred; Dümbgen, Lutz and Suter, Beat

Subjects:

500 Science > 510 Mathematics
500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

1754-8403

Publisher:

Company of Biologists Ltd.

Language:

English

Submitter:

Lutz Dümbgen

Date Deposited:

12 Dec 2014 10:51

Last Modified:

26 Jun 2016 01:56

Publisher DOI:

10.1242/dmm.016907

PubMed ID:

25431422

Uncontrolled Keywords:

Xeroderma pigmentosum, Cell cycle synchronization, Xpd, Mitotic defect

BORIS DOI:

10.7892/boris.60936

URI:

https://boris.unibe.ch/id/eprint/60936

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