title: The function of CUX1 in oxidative DNA damage repair is needed to prevent premature senescence of mouse embryo fibroblasts.
abstract: Despite having long telomeres, mouse embryo fibroblasts (MEFs) senesce more rapidly than human diploid fibroblasts because of the accumulation of oxidative DNA damage. The CUX1 homeodomain protein was recently found to prevent senescence in RAS-driven cancer cells that produce elevated levels of reactive-oxygen species. Here we show that Cux1-/- MEFs are unable to proliferate in atmospheric (20%) oxygen although they can proliferate normally in physiological (3%) oxygen levels. CUX1 contains three domains called Cut repeats. Structure/function analysis established that a single Cut repeat domain can stimulate the DNA binding, Schiff-base formation, glycosylase and AP-lyase activities of 8-oxoguanine DNA glycosylase 1, OGG1. Strikingly and in contrast to previous reports, OGG1 exhibits efficient AP-lyase activity in the presence of a Cut repeat. Repair of oxidative DNA damage and proliferation in 20% oxygen were both rescued in Cux1-/- MEFs by ectopic expression of CUX1 or of a recombinant Cut repeat protein that stimulates OGG1 but is devoid of transcription activation potential. These findings reinforce the causal link between oxidative DNA damage and cellular senescence and suggest that the role of CUX1 as an accessory factor in DNA repair will be critical in physiological situations that generate higher levels of reactive oxygen species.
authors: Goodman Cancer Centre, McGill University, Montreal, Quebec H3A 1A3, Canada.
authors: Zubaidah M
authors: ZM
authors: Ramdzan
authors: Goodman Cancer Centre, McGill University, Montreal, Quebec H3A 1A3, Canada.|Department of Biological Sciences, Presidency University, Kolkata 700073, India.
authors: Ranjana
authors: R
authors: Pal
authors: Goodman Cancer Centre, McGill University, Montreal, Quebec H3A 1A3, Canada.|Department of Biochemistry, McGill University, Montreal, Quebec H3A 1A3, Canada.
authors: Simran
authors: S
authors: Kaur
authors: Goodman Cancer Centre, McGill University, Montreal, Quebec H3A 1A3, Canada.
authors: Lam
authors: L
authors: Leduy
authors: Goodman Cancer Centre, McGill University, Montreal, Quebec H3A 1A3, Canada.
authors: Ginette
authors: G
authors: Bérubé
authors: Goodman Cancer Centre, McGill University, Montreal, Quebec H3A 1A3, Canada.|Department of Biochemistry, McGill University, Montreal, Quebec H3A 1A3, Canada.
authors: Sayeh
authors: S
authors: Davoudi
authors: Goodman Cancer Centre, McGill University, Montreal, Quebec H3A 1A3, Canada.|Department of Biochemistry, McGill University, Montreal, Quebec H3A 1A3, Canada.
authors: Charles
authors: C
authors: Vadnais
authors: Goodman Cancer Centre, McGill University, Montreal, Quebec H3A 1A3, Canada.|Department of Biochemistry, McGill University, Montreal, Quebec H3A 1A3, Canada.|Department of Medicine, McGill University, Montreal, Quebec H3A 1A3, Canada.|Department of Oncology, McGill University, Montreal, Quebec H3A 1A3, Canada.
authors: Alain
authors: A
authors: Nepveu
mesh_terms: D000818:Animals; D016922:Cellular Senescence / Q000235:genetics*; D004249:DNA Damage; D004260:DNA Repair; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism; D045325:HCT116 Cells; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors
chemical_list: C080632:CUX1 protein, human; C000624101:Cux1 protein, mouse; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; D017382:Reactive Oxygen Species; D012097:Repressor Proteins; D014157:Transcription Factors