title: UHRF1 is a genome caretaker that facilitates the DNA damage response to gamma-irradiation.
abstract: BACKGROUND
  DNA double-strand breaks (DSBs) caused by ionizing radiation or by the stalling of DNA replication forks are among the most deleterious forms of DNA damage. The ability of cells to recognize and repair DSBs requires post-translational modifications to histones and other proteins that facilitate access to lesions in compacted chromatin, however our understanding of these processes remains incomplete. UHRF1 is an E3 ubiquitin ligase that has previously been linked to events that regulate chromatin remodeling and epigenetic maintenance. Previous studies have demonstrated that loss of UHRF1 increases the sensitivity of cells to DNA damage however the role of UHRF1 in this response is unclear.
  
  
  RESULTS
  We demonstrate that UHRF1 plays a critical role for facilitating the response to DSB damage caused by gamma-irradiation. UHRF1-depleted cells exhibit increased sensitivity to gamma-irradiation, suggesting a compromised cellular response to DSBs. UHRF1-depleted cells show impaired cell cycle arrest and an impaired accumulation of histone H2AX phosphorylation (gammaH2AX) in response to gamma-irradiation compared to control cells. We also demonstrate that UHRF1 is required for genome integrity, in that UHRF1-depleted cells displayed an increased frequency of chromosomal aberrations compared to control cells.
  
  
  CONCLUSIONS
  Our findings indicate a critical role for UHRF1 in maintenance of chromosome integrity and an optimal response to DSB damage.
authors.affiliation: Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, M5 S 1A8, Canada.
authors.forename: Helena
authors.initials: H
authors.lastname: Mistry
authors.affiliation: Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, M5 S 1A8, Canada.
authors.forename: Laura
authors.initials: L
authors.lastname: Tamblyn
authors.affiliation: Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, M5 S 1A8, Canada.
authors.forename: Hussein
authors.initials: H
authors.lastname: Butt
authors.affiliation: Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, M5 S 1A8, Canada.
authors.forename: Daniel
authors.initials: D
authors.lastname: Sisgoreo
authors.affiliation: Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, M5 S 1A8, Canada.
authors.forename: Aileen
authors.initials: A
authors.lastname: Gracias
authors.affiliation: Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, M5 S 1A8, Canada.
authors.forename: Meghan
authors.initials: M
authors.lastname: Larin
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore.
authors.forename: Kalpana
authors.initials: K
authors.lastname: Gopalakrishnan
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore.
authors.forename: Manoor Prakash
authors.initials: MP
authors.lastname: Hande
authors.affiliation: Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, M5 S 1A8, Canada.
authors.forename: John Peter
authors.initials: JP
authors.lastname: McPherson