Oxidative DNA damage

ROS is a major endogenous DNA damage causing source and 8-oxo-dG adduct have been mostly studied. Lipid peroxidation derived aldehydes are also risk to DNA. Different adducts produced are malondialdehyde-, propano- and etheno- consequent DNA adducts. Despite of lipid peroxidation and oxygen products, cells also carries many other reactive molecule specie that can be a basis of DNA damage, such as methylating agents. 7-methyl-guanine, 7-(2-hydroxyethyl) guanine, O6-methyl-guanine, O4-methylthymine, and, 3-methyladenine, of which O6-methylguanine is the major cause of mutations, all of these are most important adducts for DNA damage. High frequency of DNA damage occurs due to endogenous factors in contrast with exogenous damages. The high rate of endogenous DNA damage is related with a competent damage repair, important for the survival of a cell. Most of the DNA damage of endogenous nature is fixed up by BER pathway, mismatch repair and O6-methylguanine DNA methyltransferase. Dissociation of bases spontaneously is a most occurring endogenous DNA damage  type, leading to AP sites, is competently repaired by BER pathways while an enzyme MGMT, repair O6-methylguanine very efficiently. Majority of mutations arises endogenously, most of alterations in normal living cells are found to have a great similarity in between the mutational genes (HPRT) spectra in the normal individual lymphocytes from various population groups. Different studies suggest that mainly the mutations are caused by either due to endogenous mutagenesis mechanisms/pathways or influences of ubiquitous environmental. Adduct levels have been found to vary with gender, individual features and ethnicity. So, for sexual category, females have been found to have DNA adducts levels raised from the yield of lipid peroxidation in WBCs (White blood cells) DNA subsequent using up of PUFAs. It is also true for exogenous levels of adducts, as women smokers have been found to contain high massive DNA adducts in lung DNA than in gentleman smokers. Average levels of 8-oxo-dG ranges from 0.1- 40 adducts per 105 dG residues and reduced levels have been observed in the population of Japan, in comparison to populations Western countries. Both exogenous and endogenous processes results 8-Hydroxyguanine, so differences can be reflected by environmental, genetic factors or/and changes in sampling and analytical techniques. Changes takes place between individuals in endogenous DNA damage intensity and threat of unstructured tumour formation can be expected. Some endogenously natured genotoxic materials are produced by more than one mechanism or pathway. When keeping in view of chemopreventive approach it might be essential to identify metabolic pathway that dominate in producing a given material. For example decomposition of lipid hydroperoxides, autoxidation of sugars and oxidative deoxyribose yields reactive aldehyde glyoxal. In addition, particular adducts also exists which can be produced by a number of various genotoxic material. For example, M1G adduct can be produced by MDA and through base propenals. We know, M1G is basically produced via base propenals instead of MDA  might be associated with chemoprevention.  DNA damage caused by either exogenous or endogenous is difficult to identify. Some mutagens of exogenous nature can also occur endogenously and some exogenous materials or reactive species can be chemically varies from endogenous, forming the same type of DNA adducts. For example exogenous mutation causing adducts that can be present endogenously are also exocyclic adducts produces through aldehydes crotonaldehyde and acrolein. These adducts can present exogenously as an ecological unwanted chemicals. Systemic metabolic homeostasis could be affected by effecting endocrine system and cellular metabolic processes. Specifically, damage response activation in some tissues can affect the role of important metabolic organs by provoking insulin resistance. Better perceptive of general DNA damage response can help in the development of novel strategies for therapeutics of metabolic defects. Our cells have different kinds of systems to control nutrient availability activation to maintain homeostasis and cells have active DNA repair mechanism to keep away from harmful genomic instability. Studies proved that two discrete cellular activities are extremely synchronized. 

 

We presented some of regulatory molecules with dual functionalities in repairing or causing DNA damage in this review. It includes sirtuins, p53 and ATM. Upcoming studies are looking forward to discover additional factors that plays their role in different processes and shed light on DNA damage role in metabolic diseases. Cellular responses are characterized through the degree DNA damage is another feature of DNA damage. For example, a reversible cell cycle can be arrested to permit damage repair in case of mild DNA damage, while reasonable to cruel DNA scratch causes senescence or cell death which stops tumorigenic damaged cells from accumulating DNA damage. However, an extremely delayed DNA damage response can have a harmful impact on metabolic processes and on tumorigenesis by autonomous or/and non-autonomous cell processes and pathways. Similarly, regulation of glucose metabolism physiology requires activation of normal p53. By holding back activation of dysregulated p53 is useful for reducing insulin resistance related to dietary obesity, signifying that by fine tuning damage response of a DNA is significant for the treatment and prevention of many  metabolic diseases.