UHRF1 is a genome caretaker that facilitates the DNA damage response to gamma-irradiation.
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.
Mistry
Helena
H
Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, M5 S 1A8, Canada.
Tamblyn
Laura
L
Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, M5 S 1A8, Canada.
Butt
Hussein
H
Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, M5 S 1A8, Canada.
Sisgoreo
Daniel
D
Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, M5 S 1A8, Canada.
Gracias
Aileen
A
Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, M5 S 1A8, Canada.
Larin
Meghan
M
Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, M5 S 1A8, Canada.
Gopalakrishnan
Kalpana
K
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore.
Hande
Manoor Prakash
MP
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore.
McPherson
John Peter
JP
Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, M5 S 1A8, Canada.