Mechanism of DNA break repair in germline cells

Institution:	University of California, Davis
Investigator(s):	Amitabh Nimonkar, Ph.D.
Award Cycle:	2007 (Cycle 16)	Grant #: 16FT-0069	Award: $75,000
Subject Area:	Cancer
Award Type:	Postdoctoral Fellowship Awards

Abstracts

Initial Award Abstract

Cigarette smoking is the number one cause of lung cancer. In addition to nicotine, there are about 100 more ingredients present in a cigarette, 20 of which are carcinogens, substances that cause cancer. Many of these substances are known to inflict breaks in DNA, the blueprint of life. Failure to repair such discontinuities in DNA has been strongly linked to tumor formation, including lung cancer. Here, I propose to uncover the molecular mechanism of the repair of this damage to DNA. My laboratory is at the forefront of studying double strand DNA break repair via homologous recombination, a process that ensures faithful repair of such breaks. Over the last 25 years, we have purified and characterized a number of components of this machinery, many of which have been tied to cancer. Using biochemical and biophysical tools developed in our laboratory, I propose to study two crucial components of this pathway. I choose to study these two proteins (Dmc1 and Rdh54) because they are vital for error-free recombination in germline cells, cells that are involved in reproduction. Recombination in germline cells initiates by the infliction of programmed DNA breaks, and a failure to repair such breaks are a major cause of miscarriages, still-births and cancer. Importantly, there is a strong correlation between smoking and miscarriages as well childhood cancer, thereby making the proposed work highly relevant to fatalities associated with smoking. My approach of studying the process at its fundamental level will provide deep insights into the mechanism of homologous recombination. A complete understanding of this process is necessary for developing potential targets that would help to eradicate the lethal effect of smoking-induced diseases. My study has the added benefit of not requiring human subjects or the sacrifice of model animals.

Publications

Human exonuclease 1 and BLM helicase interact to resect DNA and initiate DNA repair.
Periodical: Proceedings of the National Academy of Sciences of the United States of America			Index Medicus:
Authors: Nimonkar AV, Ozsoy AZ, Genschel J, Modrich P, Kowalczykowski SC,				ART
Yr: 2008	Vol: 105	Nbr: 44	Abs:	Pg: 16906-169011

Second-end DNA capture in double-strand break repair to form complement-stabilized joint molecules.
Periodical: Proceedings of the National Academy of Sciences of the United States of America			Index Medicus:
Authors: Nimonkar AV, Sica RA, Kowalczykowski SC,				ART
Yr: 2009	Vol: 106	Nbr: 9	Abs:	Pg: 3077-3082

Human exonuclease 1 and BLM helicase interact to resect DNA and initiate DNA repair.
Periodical: Proceedings of the National Academy of Sciences of the United States of America			Index Medicus:
Authors: Nimonkar AV, Ozsoy AZ, Genschel J, Modrich P, Kowalczykowski SC,				ART
Yr: 2008	Vol: 105	Nbr: 44	Abs:	Pg: 16906-169011

Second-end DNA capture in double-strand break repair to form complement-stabilized joint molecules.
Periodical: Proceedings of the National Academy of Sciences of the United States of America			Index Medicus:
Authors: Nimonkar AV, Sica RA, Kowalczykowski SC,				ART
Yr: 2009	Vol: 106	Nbr: 9	Abs:	Pg: 3077-3082