%0 Journal Article
%T UHRF1 is a genome caretaker that facilitates the DNA damage response to ¦Ã-irradiation
%A Helena Mistry
%A Laura Tamblyn
%A Hussein Butt
%A Daniel Sisgoreo
%A Aileen Gracias
%A Meghan Larin
%A Kalpana Gopalakrishnan
%A Manoor Hande
%A John McPherson
%J Genome Integrity
%D 2010
%I BioMed Central
%R 10.1186/2041-9414-1-7
%X We demonstrate that UHRF1 plays a critical role for facilitating the response to DSB damage caused by ¦Ã-irradiation. UHRF1-depleted cells exhibit increased sensitivity to ¦Ã-irradiation, suggesting a compromised cellular response to DSBs. UHRF1-depleted cells show impaired cell cycle arrest and an impaired accumulation of histone H2AX phosphorylation (¦ÃH2AX) in response to ¦Ã-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.Our findings indicate a critical role for UHRF1 in maintenance of chromosome integrity and an optimal response to DSB damage.UHRF1 (also known as Np95 and ICBP90) was originally identified as a protein whose subcellular expression pattern coincided with sites of DNA replication [1-3]. Further studies supported a role for this protein in S phase progression, particularly in replication of heterochromatin regions surrounding centromeres known as pericentric heterochromatin [4-6]. This role in heterochromatin replication and maintenance is linked to the ability of UHRF1 to facilitate several epigenetic modifications of histones and DNA [5-7]. UHRF1 binds to and ubiquitinates histone H3 [7,8] and facilitates deacetylation of lysine 8, 12, and 16 of heterochromatin histone H4 [6,9]. The SET and RING associated (SRA) domain of UHRF1 binds to hemi-methylated DNA and plays a crucial role in copying pre-existing methylation patterns onto newly replicated DNA by recruiting the DNA methyltransferase Dnmt1 to replication sites [10-14]. In addition to its function in duplicating DNA methylation patterns, UHRF1 binds to histone H3 tri-methylated at lysine 9 (H3K9me3) and plays a role in maintaining this histone modification in heterochromatin [7]. A recent study has pointed to the importance of a tandem tudor domain for UHRF1 binding to H3K9me3 [15].Several studies have now identified a role for
%U http://www.genomeintegrity.com/content/1/1/7