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A Role for Np95 in Genome Integrity Maintenance.
Author(s) -
Mistry Helena Sumantrai
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.878.4
Subject(s) - heterochromatin , dna damage , biology , histone , genome instability , dna repair , heterochromatin protein 1 , microbiology and biotechnology , g2 m dna damage checkpoint , dna methylation , dna , chromatin , cell cycle checkpoint , cell cycle , genetics , cell , gene expression , gene
Np95 (also known as Uhrf1) is a proliferation‐associated E3 ubiquitin ligase that participates in maintenance of DNA methylation and histone H3 lysine 9 trimethylation trimeH3K9) associated with heterochromatin. Although cells deficient in Np95 have previously been shown to exhibit greater sensitivity to DNA damaging agents, the role of this protein in the cellular response to DNA damage is unknown. Here we report that Np95 is critical for the maintenance of genome integrity. In the absence or presence of DNA damaging agents, Np95 deficiency leads to an increase in the number of cells with chromosomal instability and elevated levels of γH2AX, a cellular marker that signifies the presence of DNA double strand breaks. Although H2AX status has previously been shown to impact checkpoint activation, Np95 deficient cells exhibit intact checkpoint activation compared to wild‐type cells. Furthermore, DNA damage signalling pathways that activate Chk2 and FancD2 are intact in Np95 deficient cells. Loss of Np95 results in a redistribution of focal trimeH3K9 staining to the nuclear periphery. We observed that (ii) focal staining of heterochromatin protein HP1β but not HP1α dissipates following DNA damage and (ii) this loss of focal HP1β staining is accentuated in Np95 deficient cells. Our findings indicate that maintenance of heterochromatin by Np95 is crucial for genome integrity and protection from DNA damage.