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  • Mechanisms of DNA damage, repair Living organisms are continuously exposed to a myriad of DNA damagi

    Release date:2023-11-16

    Living organisms are continuously exposed to a myriad of DNA damaging agents that can impact health and modulate disease-states. However, robust DNA repair and damage-bypass mechanisms faithfully protect the DNA by either removing or tolerating the damage to ensure an overall survival. Deviations in this fine-tuning are known to destabilize cellular metabolic homeostasis, as exemplified in diverse cancers where disruption or deregulation of DNA repair pathways results in genome instability. Because routinely used biological, physical and chemical agents impact human health, testing their genotoxicity and regulating their use have become important. In this introductory review, we will delineate mechanisms of DNA damage and the counteracting repair/tolerance pathways to provide insights into the molecular basis of genotoxicity in cells that lays the foundation for subsequent articles in this issue.

    Preserving genomic sequence information in living organisms is important for the perpetuation of life. At the same time, mutagenesis plays an indispensible part in its maintenance and evolution, while also contributing to cancer, certain human diseases and aging. It is known that DNA, the basic unit of inheritance, is an intrinsically reactive molecule and is highly susceptible to chemical modifications by endogenous and exogenous agents. Furthermore, the DNA polymerases engaged in DNA replication and repair make mistakes, thereby burdening cells with potentially disadvantageous mutations. However, cells are equipped with intricate and sophisticated systems—DNA repair, damage tolerance, cell cycle checkpoints and cell death pathways—that collectively function to reduce the deleterious consequences of DNA damage.

    Cells respond to DNA damage by instigating robust DNA damage response (DDR) pathways, which allow sufficient time for specified DNA repair pathways to physically remove the damage in a substrate-dependent manner. At least five major DNA repair pathways—base excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR), homologous recombination (HR) and non-homologous end joining (NHEJ)—are active throughout different stages of the cell cycle, allowing the cells to repair the DNA damage. A few specific lesions can also be removed by direct chemical reversal and interstrand crosslink (ICL) repair. These repair processes are key to maintaining genetic stability in cells. In addition, certain types of DNA damage are substrates for the DNA damage tolerance pathways. In higher eukaryotes, for example, a well-orchestrated group of five main translesion synthesis (TLS) polymerases—REV1, POL ζ, POL η, POL κ and POL ι—bypass the damage to enable the continuation of replication, but with the possibility of a concurrent introduction of an incorrect base that can be fixed into a mutation in the subsequent round of replication. Under the circumstances, when the damaged DNA persists, programmed cell death or apoptosis, a regulatory response to DNA damage, is activated to get rid of cells with extensive genome instability.

    Not surprisingly, in many cancers, DNA repair, DNA damage tolerance and DDR pathways are disrupted or deregulated, which increases mutagenesis and genomic instability, thereby promoting cancer progression. Likewise, aging is attributed to attrition of chromosomal ends and failing capacities of a combination of these pathways. Other diseases, such as neurodegenerative disorders, result from a combinatorial failure of more than one of these processes. The 2015 Nobel Prize in Chemistry to Drs. Lindahl, Modrich and Sancar highlights the importance of mechanisms of DNA damage and repair and their implications for human health. In this review we will discuss the details of various types and mechanisms of DNA damage and the compensatory repair and tolerance pathways.

    DNA damage can be categorized into two main classes based on its origin: endogenous and exogenous. The majority of the endogenous DNA damage arises from the chemically active DNA engaging in hydrolytic and oxidative reactions with water and reactive oxygen species (ROS), respectively, that are naturally present within cells. Such inherently predisposed reactions of DNA with molecules from its immediate surroundings fuel the development of hereditary diseases and sporadic cancers. Exogenous DNA damage, on the other hand, occurs when environmental, physical and chemical agents damage the DNA. Examples include UV and ionizing radiation, alkylating agents, and crosslinking agents. We offer here a brief summary of the main endogenous and environmental agents that produce the different classes of DNA damage that then become substrates for the specific DNA repair pathways discussed in the subsequent section.