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Dis Model Mech. 2015 Jan;8(1):81-91. doi: 10.1242/dmm.016907. Epub 2014 Nov 27.

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

Author information

1
Institute of Cell Biology, University of Bern, 3012 Bern, Switzerland.
2
Department of Biology, Philipps-University Marburg, 35032 Marburg, Germany.
3
Department of Clinical Research, University of Bern, 3010 Bern, Switzerland.
4
Institute of Mathematical Statistics and Actuarial Science, University of Bern, 3012 Bern, Switzerland.
5
Institute of Cell Biology, University of Bern, 3012 Bern, Switzerland. beat.suter@izb.unibe.ch.

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.

KEYWORDS:

Cell cycle synchronization; Mitotic defect; Xeroderma pigmentosum; Xpd

PMID:
25431422
PMCID:
PMC4283652
DOI:
10.1242/dmm.016907
[Indexed for MEDLINE]
Free PMC Article

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