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DNA damage and Metabolic diseases



DNA carries the genetic information and it is necessary to maintain its stability and integrity for the survival of any living organism. Any change in DNA structure can cause DNA damage and it can cause ageing, carcinogenesis and mutagenesis. DNA damage can be caused by many factors which include any chemical alteration in bases, change or breakage in DNA backbone or insertion or deletion of any base. Released from different metabolic processes, alkylating agents, reactive carbonyl, nitrogen (RNS) and oxygen species (ROS), lipid peroxidation products and hydrolysis are the main compounds that cause DNA damage. About 1000 to 100000 DNA damage occurs per cell in human genome per day. Most of DNA damage is repaired by different enzymes, proteins and pathways naturally occurring in organism body, but still this damage repair is not 100%, which causes different problems and diseases. Accumulation of damaged DNA in replication cells (i.e colon cell line cells) can cause replication errors and ultimately leads to serious issues such as cancer. Similarly, accumulation of damaged DNA in non-replicating cells can cause ageing of muscle and brain cells.





DNA can be damaged either endogenously or exogenously. Most of damages are of endogenous nature and causes similar damages as those produced by exogenous or environmental factors. Reactive nitrogen and oxygen species are the endogenous sources of DNA damage. These free radicals are produced by different enzymes for different activities such as myeloperoxidase and NADPH oxidase produce reactive oxygen species to kill invading pathogens and for cell signaling purpose, nitric oxide synthases produces reactive NO. At some frequencies, mitochondrial electrons can be transferred to oxygen and produce hydrogen peroxide and superoxide, which in turn can produce hydroxyl radicals and damage biomolecules like DNA. 




Oxidative stress is one of the DNA damaging cause which can break backbone of DNA molecule (made up of sugar-phosphate) and interrupt replication or transcription by breaking single DNA strands. When such breaks occur at a high density, they can also break nearby double strands on opposite sides. Such damage is repaired during S phase of cell division (homologous recombination) or non-homologous in cell division phases in which sister chromatid is not available for repair, such damage response is known as DNA damage response. This DNA damage response is a framework of different repair and signaling pathways which detect and activate repair pathways through genotoxic stress.




When damages occurs either collapsed replication folk or breakdown of DNA double strand, some proteins such as serine/threonine kinases ATR or ATM initiate a sequence of cellular responses to determine the cell fate by cell cycle arrest or recruitment of damage repair factors. ATR or ATM targets p53 (tumor suppressor protein) and activates genes responsible for cell death or senescence. DNA damage also activates some other proteins to deplete NAD+ and ATP to decide cell fate indirectly, such as PARP (ADP ribose polymerase). Oxidative stress plays an important role in diabetes growth and many complications associated with it such as cardiovascular and microvascular. Diabetic abnormality of metabolic process causes overproduction of mitochondrial superoxide which plays a vital and major intermediary of diabetes tissue damage. It activates 5 different complication pathways of pathogenesis and direct inactivation of prostacyclin synthase and eNOS.




Although, DNA damages are repaired by many overlapping repair pathways to remove damaged DNA and it also determines cell fate. Nucleotide excision repair pathways repair oxidative base damage and base excision repair pathway removes helical distortions in DNA structure, damages caused by ultra violet radiations and other exogenous oxidative damages. Along with these pathways, DNA Mismatch repair and DNA strand break repair pathways also important in repairing damaged DNA.This review is aimed to present  endogenous or exogenous molecules or causes that can damage DNA and metabolic disease associated with DNA damage including diabetes, cardiovascular disease etc.
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