Temporally distinct roles of ATM and ROS in genotoxic- stress-dependent induction and maintenance of cellular senescence

Nair, Raji R and Bagheri, Meisam and Saini, Deepak Kumar (2015) Temporally distinct roles of ATM and ROS in genotoxic- stress-dependent induction and maintenance of cellular senescence. In: JOURNAL OF CELL SCIENCE, 128 (2). pp. 342-353.

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Abstract

Cells exposed to genotoxic stress induce cellular senescence through a DNA damage response (DDR) pathway regulated by ATM kinase and reactive oxygen species (ROS). Here, we show that the regulatory roles for ATM kinase and ROS differ during induction and maintenance of cellular senescence. Cells treated with different genotoxic agents were analyzed using specific pathway markers and inhibitors to determine that ATM kinase activation is directly proportional to the dose of the genotoxic stress and that senescence initiation is not dependent on ROS or the p53 status of cells. Cells in which ROS was quenched still activated ATM and initiated the DDR when insulted, and progressed normally to senescence. By contrast, maintenance of a viable senescent state required the presence of ROS as well as activated ATM. Inhibition or removal of either of the components caused cell death in senescent cells, through a deregulated ATM-ROS axis. Overall, our work demonstrates existence of an intricate temporal hierarchy between genotoxic stress, DDR and ROS in cellular senescence. Our model reports the existence of different stages of cellular senescence with distinct regulatory networks.

Item Type:	Journal Article
Publication:	JOURNAL OF CELL SCIENCE
Publisher:	COMPANY OF BIOLOGISTS LTD
Additional Information:	Copy right for this article belongs to the COMPANY OF BIOLOGISTS LTD, BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND
Keywords:	Cellular senescence; DNA damage response; Reactive oxygen species; ATM kinase
Department/Centre:	Division of Biological Sciences > Molecular Reproduction, Development & Genetics
Date Deposited:	04 Mar 2015 12:42
Last Modified:	04 Mar 2015 12:42
URI:	http://eprints.iisc.ac.in/id/eprint/50988

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