title: Defective Hfp-dependent transcriptional repression of dMYC is fundamental to tissue overgrowth in Drosophila XPB models.
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.
authors.affiliation: Department of Anatomy and Neuroscience, University of Melbourne, Parkville, Melbourne 3010, Australia.
authors.forename: Jue Er Amanda
authors.initials: JE
authors.lastname: Lee
authors.affiliation: Department of Anatomy and Neuroscience, University of Melbourne, Parkville, Melbourne 3010, Australia.
authors.forename: Naomi C
authors.initials: NC
authors.lastname: Mitchell
authors.affiliation: Department of Anatomy and Neuroscience, University of Melbourne, Parkville, Melbourne 3010, Australia.
authors.forename: Olga
authors.initials: O
authors.lastname: Zaytseva
authors.affiliation: Department of Anatomy and Neuroscience, University of Melbourne, Parkville, Melbourne 3010, Australia.
authors.forename: Arjun
authors.initials: A
authors.lastname: Chahal
authors.affiliation: Department of Anatomy and Neuroscience, University of Melbourne, Parkville, Melbourne 3010, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Mendis
authors.affiliation: Aix-Marseille University, F-13284 Marseille, France.
authors.forename: Amandine
authors.initials: A
authors.lastname: Cartier-Michaud
authors.affiliation: Department of Anatomy and Neuroscience, University of Melbourne, Parkville, Melbourne 3010, Australia.
authors.forename: Linda M
authors.initials: LM
authors.lastname: Parsons
authors.affiliation: Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne Victoria 3002, Australia.
authors.forename: Gretchen
authors.initials: G
authors.lastname: Poortinga
authors.affiliation: Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Levens
authors.affiliation: 1] Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne Victoria 3002, Australia [2] Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, The Australian National University, Canberra Australian Capital Territory 2600, Australia.
authors.forename: Ross D
authors.initials: RD
authors.lastname: Hannan
authors.affiliation: Department of Anatomy and Neuroscience, University of Melbourne, Parkville, Melbourne 3010, Australia.
authors.forename: Leonie M
authors.initials: LM
authors.lastname: Quinn
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000235:genetics*; D047369:Chromatin Immunoprecipitation; D004265:DNA Helicases / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D029721:Drosophila Proteins / Q000235:genetics*; D004331:Drosophila melanogaster; D005786:Gene Expression Regulation; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics*; D007150:Immunohistochemistry; D009154:Mutation; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic; D014983:Xeroderma Pigmentosum / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D020662:Guanine Nucleotide Exchange Factors; C484363:Hfp protein, Drosophila; C102284:Myc protein, Drosophila; D014157:Transcription Factors; C078672:hay protein, Drosophila; D004265:DNA Helicases