DNA lesions at specific positions have been shown to be associated with the induction of heritable mutations. The accumulation of such erroneous elements in the genetic code may ultimately result in cellular aberrations, compromising structure, function, and viability. Such adverse alterations may also form the genetic basis of a variety of diseases. In fact, chromosomal aberrations and germline mutations often lead to the loss of function of tumor suppressor genes and / or those coding for essential cell cycle checkpoint proteins, which may result in uncontrollable cellular proliferation and thereby, the development of disease indications, such as cancer.
Researchers have estimated the total number of DNA damaging events per cell, per day, to be around 60,000. Further extrapolations suggest that there are about 3×1017 DNA damaging events taking place, per hour, in the human body. However, in eukaryotes, the likely adverse events / health implications associated with DNA damage are largely prevented by a robust DNA repair system.
DNA damage can be caused by a series of chemical events, such as hydrolysis, interactions with reactive oxygen species and other reactive metabolites, which are consequences of exposure to both exogenous and endogenous factors. In higher eukaryotes, various DNA repair mechanism are involved in the repair of the specific damage caused by both, exogenous and endogenous factors. Further, they also possess an elaborate and highly coordinated DNA damage response (DDR) system. This system is responsible for identifying damaged DNA segments, tagging DNA lesions and signaling their presence in the genome, and in turn mediating a corrective response, which usually results in either the development of tolerance or DNA repair. The response system is comprised of a family of molecular entities (including sensors, transducers and effectors) that facilitate and / or mediate the repair process. Common responses to DDR signaling include activation of transcription, cell cycle control, DNA repair pathways, apoptosis, senescence and cell death. The various DNA damage tolerance and repair mechanisms in eukaryotes have been briefly described below:
- DNA Damage Tolerance: Despite the presence of several repair mechanisms, it is likely that certain errors that are improperly repaired or entirely unrepaired, may interfere with the DNA replication process. This results in the collapse of the replication fork, further leading to genomic instability. In such cases, the DNA damage tolerance pathway gets activated, and recruits a specialized low fidelity translesion synthesis polymerase capable of bypassing lesions and leaving them for repair at a later time point. This pathway restarts the halted replication fork, and is therefore, integral to the completion of the replication process, despite the presence of lesions in DNA. Once the replication process is completed, all the remaining lesions are tagged and subjected to repair. This process is primarily convened by two specialized pathways, namely the translesion synthesis (TLS) and template switching (TS) pathways.
- DNA Damage Repair (DDR): This system involves a coordinated sequence of events, involving the detection of DNA damage points (by sensor proteins), followed by the transduction of information ataxia-telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3-related (ATR) and the subsequent repair of damaged DNA segments.
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