title: Sirtuin 7 promotes cellular survival following genomic stress by attenuation of DNA damage, SAPK activation and p53 response.
abstract: Maintaining the genomic integrity is a constant challenge in proliferating cells. Amongst various proteins involved in this process, Sirtuins play a key role in DNA damage repair mechanisms in yeast as well as mammals. In the present work we report the role of one of the least explored Sirtuin viz., SIRT7, under conditions of genomic stress when treated with doxorubicin. Knockdown of SIRT7 sensitized osteosarcoma (U2OS) cells to DNA damage induced cell death by doxorubicin. SIRT7 overexpression in NIH3T3 delayed cell cycle progression by causing delay in G1 to S transition. SIRT7 overexpressing cells when treated with low dose of doxorubicin (0.25 µM) showed delayed onset of senescence, lesser accumulation of DNA damage marker γH2AX and lowered levels of growth arrest markers viz., p53 and p21 when compared to doxorubicin treated control GFP expressing cells. Resistance to DNA damage following SIRT7 overexpression was also evident by EdU incorporation studies where cellular growth arrest was significantly delayed. When treated with higher dose of doxorubicin (>1 µM), SIRT7 conferred resistance to apoptosis by attenuating stress activated kinases (SAPK viz., p38 and JNK) and p53 response thereby shifting the cellular fate towards senescence. Interestingly, relocalization of SIRT7 from nucleolus to nucleoplasm together with its co-localization with SAPK was an important feature associated with DNA damage. SIRT7 mediated resistance to doxorubicin induced apoptosis and senescence was lost when p53 level was restored by nutlin treatment. Overall, we propose SIRT7 attenuates DNA damage, SAPK activation and p53 response thereby promoting cellular survival under conditions of genomic stress.
authors.affiliation: Laboratory of Cancer Biology, Centre for DNA Fingerprinting and Diagnostics, Hyderabad, Telangana, 500001, India.
authors.forename: Shashi
authors.initials: S
authors.lastname: Kiran
authors.affiliation: Laboratory of Cancer Biology, Centre for DNA Fingerprinting and Diagnostics, Hyderabad, Telangana, 500001, India.
authors.forename: Vineesha
authors.initials: V
authors.lastname: Oddi
authors.affiliation: Laboratory of Cancer Biology, Centre for DNA Fingerprinting and Diagnostics, Hyderabad, Telangana, 500001, India; Laboratory of Cancer Cell Biology, Department of Research, Institute of Liver and Biliary Sciences, Delhi 110070, India. Electronic address: gayatrirama1@gmail.com.
authors.forename: Gayatri
authors.initials: G
authors.lastname: Ramakrishna
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle; D049109:Cell Proliferation; D004249:DNA Damage / Q000235:genetics*; D005434:Flow Cytometry; D042822:Genomic Instability; D006801:Humans; D051379:Mice; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism*; D041681:NIH 3T3 Cells; D012516:Osteosarcoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D034741:RNA, Small Interfering / Q000235:genetics; D037761:Sirtuins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D034741:RNA, Small Interfering; C510661:SIRT7 protein, human; D016159:Tumor Suppressor Protein p53; D048055:Mitogen-Activated Protein Kinase 8; D037761:Sirtuins
keywords: Cell cycle; Cell death; DNA damage; Doxorubicin; SIRT7; Senescence; p53