Keeping DNA in good shape

December 1, 2014

A stitch in time saves nine, goes the old saying. And here a team of scientists at Indian Institute of Science study RAGs (recombination activating genes) to understand the stitching and unstitching of the DNA, which in certain ways leads to genomic instability and cancer.

The RAG complex consists of two genes, RAG1 and RAG2. These genes produce the RAG proteins – RAG1 and RAG2 — which are expressed in the B and T cells of our immune system. The B and T cells help in locating and dealing with foreign substances that enter our bodies like bacteria and other microbes. The cells can recognise foreign bodies using proteins on their surfaces. The RAG gene complex helps in the generation of these surface proteins.

The high number of surface proteins that need to be produced sometimes leads to genomic instability and “chromosomal translocations” – rearrangement of bits of the chromosome, which can lead to incorrect arrangement of genes. This can lead to diseases like lymphoma and leukemia.

In a previous study, Dr. Sathees C Raghavan and Rupa Kumari showed that RAG proteins cleave DNA when they spot a particular sequence of nucleotides. In this paper, they have focussed on studying the factors that can regulate DNA cleavage efficiency of the RAG proteins. This can improve our understanding of how the DNA cleaving activity of these genes is turned on and off.

They found that apart from the sequence of a particular DNA complex, the sequence of the regions surrounding it are important in determining where the RAG proteins bind and where they cleave. The presence of cytosine and thymine in a single stranded region of the DNA complex dictates the position of nicking. A minimum of two cytosines are required for the RAGs cleavage efficiency. The deletion of certain sequences could result in the loss of sequence specific nuclease activity of RAG but it retains its structure specific nuclease activity.

The further understanding of these factors which regulate the stability of the above mentioned DNA complex could help us decipher the mutations that act as the root causes leading to cancers like lymphoma and leukemia.

The paper has been published online on 14th November in The FEBS Journal. http://onlinelibrary.wiley.com/doi/10.1111/febs.13121/abstract

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Taking help from ageing cells to suppress tumours

December 8, 2014

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.

The paper will be published in the Journal of Cell Science and appeared online on 21st November. http://jcs.biologists.org/content/early/2014/11/20/jcs.159517.abstract

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