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Taking help from ageing cells to suppress tumours

As cells grow older, their DNA gets damaged. Depending on the extent of damage, the cell can repair the DNA and continue its life, or self destruct and die. A molecule called ATM kinase is involved in this decision making process.

Deepak Saini’s lab at IISc has delineated the role of ATM kinase in this important process. The extent of DNA damage either triggers activation of cancer causing genes, or deactivation of tumour suppressor genes. Both these processes can initiate uncontrollable multiplication of cells, leading to cancer. The other possible outcome of DNA damage, especially if very severe, is cell death. The decision of the cell’s fate lies in the hands of the genetic errors accumulated. If the errors cannot be repaired, or can be detrimental if left unrepaired, the cells enter cellular senescence, which is basically ageing. Cell function deteriorates and ageing of the organism is the inevitable result.

The senescent condition of the cells depend on their respective abilities to maintain a persistent DNA damage state without inducing death or repair. There are a number of molecules like ATM kinase and ROS (reactive oxygen species) that play a critical role in regulating cell fate after the genomic damage.

Cellular senescence can be divided into two distinct phases – initiation or early senescence and the maintenance of senescence. The present research delineates the roles of ATM kinase in the initiation of senescence and importance of ROS in maintaining senescence. ATM kinase is one of the key proteins which decides the fate of a cell; it also acts as a quantitative sensor for DNA damage. When DNA damage is not so severe, the cell repairs its DNA and continues growth; in severe damaged states, the cell dies.

In the intermediate stages of damage, the cell enters the senescent stage activated by ATM kinase. “Our studies show that senescence or aging is one of the cell fates in response to DNA damage and the decision is dependent on the dose of damage and ATM kinase protein. Aged cells generate free radicals which is critical in maintaining their status quo”, said Dr. Saini.

Since the other two alternatives after DNA damage – death and cancer – are obviously harmful, a possible way to push a cell toward senescence instead of the other options can have possible therapeutic value. Cell senescence can be induced in tumour and cancer cells by using a sub-lethal dose of stress, by agents like gamma rays, hydrogen peroxide etc. which triggers the DNA damage response leading to senescence. Further research on this could help us devise a very simple yet attractive tumour suppressing mechanism.

About the authors:

Dr. Deepak Kumar Saini is Assistant Professor at the Department of Molecular Reproduction, Development and Genetics, IISc, Bangalore. Raji R Nair and Meisam Bagheri are PhD students at Dr. Saini’s lab.

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The paper will be published in the Journal of Cell Science and appeared online on 21st November.