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Selenoprotein H suppresses cellular senescence through genome maintenance and redox regulation
Author(s) -
Wu Ryan T.Y.,
Mattson Elliot,
Cheng WenHsing
Publication year - 2013
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.27.1_supplement.860.12
Subject(s) - small hairpin rna , gene knockdown , dna damage , oxidative stress , microbiology and biotechnology , chemistry , biology , cancer research , apoptosis , biochemistry , dna
Oxidative stress and persistent DNA damage can lead to cellular senescence and aging. Selenoprotein H (SelH) is known to carry redox domains and to transactivate a gene for glutathione biosynthesis. To determine the role of SelH in genome maintenance, we employed SelH and scrambled shRNA knockdown in MRC‐5 human diploid fibroblast or the immortal HeLa cells. SelH shRNA MRC‐5 cells showed more pronounced phenotypic induction of β‐galactosidase expression, autofluorescence, growth inhibition, and ATM pathway activation (γH2AX and phospho‐ATM on Ser‐1981 induction) as compared to scrambled shRNA MRC‐5 cells. Moreover, the increased expression of phospho‐ATM on Ser‐1981 and γH2AX by H 2 O 2 treatment (20 μM) was persistent in SelH shRNA but reversed in the scrambled shRNA MRC‐5 cells 1–5 days after recovery. Interestingly, the slow proliferation in SelH shRNA MRC‐5 cells can be alleviated in the presence of ATM kinase inhibitors KU 55933 and KU 60019, by p53 shRNA knockdown, or by maintaining the cells in 3% O 2 incubator (vs. ambient O 2 ). Results from colony forming assays indicated that SelH shRNA HeLa cells were hypersensitive to paraquat and H 2 O 2 but not to other clastogens including hydroxyurea, neocarzinostatin or camptothecin. In conclusion, SelH protects against cellular senescence specifically to oxidative stress through a genome maintenance pathway involving ATM and p53. Grant Funding Source : UMCP