A range of causes, from excess sunlight to poor eating habits, can potentially trigger events leading to damage of DNA – the long, double-stranded molecules that contain our genetic code. But our ever-efficient human body has developed elaborate DNA repair mechanisms to combat such situations. Such processes involve a wide range of cellular machinery working in tandem to repair the damage. If everything else fails, there is even a backup in place – nudging the damaged cell into committing suicide before others are affected. Studying such repair mechanisms is important, because some faults in DNA repair could lead to uncontrolled cell division, resulting in cancer.
Dr. Sathees Raghavan, an Associate Professor in the Department of Biochemistry at IISc, Bangalore, is interested in studying such DNA repair mechanisms, particularly those involving breaks in both strands of the DNA. He has recently published his group’s findings of an extensive study investigating the role of a lesser-understood mechanism known as MMEJ or Microhomology-Dependent Alternative End Joining.
The study by Prof. Raghavan’s group on MMEJ was published in Cell Death and Disease, a journal from the Nature Publishing Group. It sheds light on the cellular conditions and molecules that this process requires to operate. Some of the molecules could directly or indirectly serve as candidate targets in the development of drugs to block this repair process, especially in cancer cells, forcing the cells to die rather than multiply.
In simplest terms, MMEJ is a sequence of events that brings about the joining of the two broken ends of DNA, as long as small portions of the genetic code on both these strands are comparable. This mechanism is not always efficient; sometimes, the strands are not matched correctly and after joining, may end up with a faulty code. If the mismatch occurs at a vital portion of the code, for instance, a part of the DNA responsible for cell division, this could lead to reckless cell division, and ultimately, cancer.
For a system evolved primarily to correct errors, it is ironic that this MMEJ mechanism itself incorporates a large number of errors into the DNA. Would it not be a better strategy for the cell to simply commit suicide, once it realizes that a strand is broken, rather than attempting to fix it and possibly generate a flawed code in the process? “Of course not,” explains Prof. Raghavan. “Given the sheer volume of cells that accumulates such breaks in both its DNA strands, if each of these cells were to commit suicide then we wouldn’t be left with much to live with.”
Under normal conditions, errors incorporated by this not-so-efficient method are comparatively negligible. However, when there are large-scale DNA breakages, they could force this mechanism to kick in at high gear. This could result, in a number of cases, in cancer.
MMEJ-based DNA repair has only come into focus of late, and even so was prominently observed only in cancerous cells when enzymes involved in the normal DNA repair machinery were absent, mutated or blocked. However, the recent study from Prof. Raghavan’s lab has demonstrated for the first time that MMEJ occurs even in normal cells.
Further research on the proteins involved and mechanisms of action is yet to follow.
About the authors:
Sathees C. Raghavan is an Associate Professor in the Department of Biochemistry, Indian Institute of Science, Bangalore. Sheetal Sharma, Saniya M Javadekar, Monica Pandey, Mrinal Srivastava and Rupa Kumari are PhD students working under the guidance of Dr. Sathees C. Raghavan at the Department of Biochemistry, IISc.
The paper first appeared online on 19 March 2015 in Cell Death and Disease http://www.nature.com/cddis/journal/v6/n3/full/cddis201558a.html
Sathees C. Raghavan, Ph.D
Tel: 080 2293 2674