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.
Highlights
Xeroderma pigmentosum (XP) is a rare recessive genetic disorder in humans that causes hyperpigmentation of the skin under sun exposure and cutaneous abnormalities
The activity of mutant Xpd in coordinating cell cycle timing during the Drosophila syncytial divisions correlated with the neurodevelopmental abnormalities and developmental growth defects observed in individuals with XP/Cockayne syndrome (CS) and with TTD
Altered interactions of the mutant Xpd with its molecular partners in larger protein complexes appear to be a risk factor for cancer susceptibility if these defects occur together with increased mitotic defects that lead to chromosomal instability
Summary
Xeroderma pigmentosum (XP) is a rare recessive genetic disorder in humans that causes hyperpigmentation of the skin under sun exposure and cutaneous abnormalities. TTD patients display developmental retardation, neurological abnormalities due to dysmyelination, and some have photosensitivity, but they do seem not to be predisposed to developing skin cancer (Hashimoto and Egly, 2009; Bergmann and Egly, 2001). TTD mutations seem to primarily cause a defect in the transcription function of TFIIH, and the severity of the transcriptional defects parallels the severity of the clinical phenotype of TTD patients (Berneburg and Lehmann, 2001). CS causes severe sun sensitivity, premature aging and severe developmental defects such as reduced body size, skeletal abnormalities and eye problems (Kraemer et al, 2007; Laugel, 2013). XP-D mutations of the combined XP/CS type have been described to uncouple the incision process from the DNA damage (Berneburg et al, 2000) and to cause UV-induced strand displacement (Godon et al, 2012)
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