No abstract

Nucleotide excision DNA repair (NER) pathway mutations cause neurodegenerative and progeroid disorders (xeroderma pigmentosum (XP), Cockayne syndrome (CS) and trichothiodystrophy (TTD)), which are inexplicably associated with (XP) or without (CS/TTD) cancer. Moreover, cancer progression occurs in certain patients, but not others, with similar C-terminal mutations in the XPB helicase subunit of transcription and NER factor TFIIH. Mechanisms driving overproliferation and, therefore, cancer associated with XPB mutations are currently unknown. Here using Drosophila models, we provide evidence that C-terminally truncated Hay/XPB alleles enhance overgrowth dependent on reduced abundance of RNA recognition motif protein Hfp/FIR, which transcriptionally represses the MYC oncogene homologue, dMYC. The data demonstrate that dMYC repression and dMYC-dependent overgrowth in the Hfp hypomorph is further impaired in the C-terminal Hay/XPB mutant background. Thus, we predict defective transcriptional repression of MYC by the Hfp orthologue, FIR, might provide one mechanism for cancer progression in XP/CS.

Animal growth requires coordination of cell growth and cell cycle progression with developmental signaling. Loss of cell cycle control is extremely detrimental, with reduced cycles leading to impaired organ growth and excessive proliferation, potentially resulting in tissue overgrowth and driving tumour initiation. Due to the high level of conservation between the cell cycle machinery of Drosophila and humans, the appeal of the fly model continues to be the means with which we can use sophisticated genetics to provide novel insights into mammalian growth and cell cycle control. Over the last decade, there have been major additions to the genetic toolbox to study development in Drosophila. Here we discuss some of the approaches available to investigate the potent growth and cell cycle properties of the Drosophila counterparts of prominent cancer genes, with a focus on the c-Myc oncoprotein and the tumour suppressor protein FIR (Hfp in flies), which behaves as a transcriptional repressor of c-Myc.