Low Penetrance Genetic Variations in DNA Repair Genes and Cancer Susceptibility

Abstract

The genetic material, DNA, which encodes genes needed for the production of essential proteins, is vulnerable to damage in a number of ways. Human DNA is assaulted on a daily basis by a variety of exogenous factors including UV light, cigarette smoke, dietary factors, and other carcinogens all of which can cause varying degrees of DNA damage and can lead to mutations. Similarly, endogenous factors such as undue DNA replication which can cause mismatches, hydrolysis leading to spontaneous DNA depurination, replication form collapse which can result in strand breaks, loss of bases because of spontaneous disintegration of chemical bonds, and DNA damage secondary to endogenous reactants such as alkyl groups, metal cations, and reactive oxygen species (ROS) which can induce base oxidation and DNA breaks also contribute to DNA damage (Branzei & Foiani, 2008; Capella et al., 2008) When DNA is damaged, an intertwined network of surveillance mechanisms will act including • Sensing and recognizing DNA damage by activation of cell cycle checkpoints, pause that permit assessment and complete of DNA processing , either DNA damage repair or processing of DNA intermediates • Up regulation a large number of genes • Programmed cell death or apoptosis when the cell is unable to repair the damage sustained and • Elicitation of multiple distinct DNA repair responses DNA damages are repaired by enzymes coded by one or more DNA repair pathways according to their structure, or their location in the cellular genome. DNA repair enzymes can be characterized as cellular proteins acting directly on damaged DNA in an attempt to restore the correct DNA sequence and structure. These relatively specialized enzymes appear to undertake the initial stages of recognition and repair of specific forms of DNA damage. Since there are various kinds of DNA damage, a variety of repair mechanisms are essential. Cells integrate DNA repair process with transcription and apoptosis through a network known as the DNA damage response (DDR) which is orchestrated by the checkpoint proteins.