Figure caption:
Mammalian DNA Damage Response. Main DNA damage repair or tolerance pathways in mammalian cells. Diverse DNA lesions caused by various DNA damaging agents are repaired by distinct but closely related mechanisms. The mammalian DNA damage response consists mainly of non-homologous end joining, homologous recombination, nucleotide excision repair, base excision repair, mismatch repair, direct reversal repair, and translesion DNA synthesis. UV, ultraviolet; DSB, double-strand break; SSB, single-strand break.
Chapter 10 – Genomic instability and aging
Academic Press, 2023
https://doi.org/10.1016/B978-0-12-823761-8.00020-3
Aging is a complex process of damage accumulation causing a functional decline. Several hallmarks of aging have been identified, of which, genomic instability plays a critical role in aging and age-related diseases and closely interacts with other hallmarks of aging. The genome is constantly challenged by exogenous DNA damaging sources, such as ionizing radiation, ultraviolet, and chemicals. But also, endogenous DNA damage caused by alkylation and hydrolysis can lead to chromosomal aberrations, mutations, and epimutations, eventually causing genomic instability and cellular dysfunction. The stressor-induced alterations include chromosomal (chromosome aneuploidy, chromosomal rearrangements, and fragile sites), genomic (increased genetic variability and mutated nucleic acid sequences), replicative (replication stress), and transcriptional impairments. In response to these damages, a wide range of sophisticated repair mechanisms have evolved to repair different types of damage to preserve genomic integrity, such as proper chromosome segregation, efficient DNA damage repair, and faithful DNA replication, to maintain normal function and promote organismal survival. Mammalian DNA damage response systems mainly comprise nonhomologous end joining, homologous recombination, nucleotide excision repair, base excision repair, mismatch repair, direct reversal repair, and translesion DNA synthesis. To ensure genomic stability there is crosstalk and redundancy between the different DNA repair pathways.
The maintenance of genome integrity. The genome is constantly challenged by chromosomal aberrations, telomere attrition, epigenetic alterations, DNA damages, etc., leading to genomic instability. DNA damage is usually caused by exogenous physical, chemical, and/or biological stressors, along with endogenous cellular processes, such as transcription, replication, replication-transcription conflicts, and reactive oxygen species (ROS). Efficient DNA repair attenuates nuclear and mitochondrial DNA damages. Except for mtDNA repair, the mitochondrial transcription factor A (TFAM) also guards mtDNA by physical interactions. Enhanced mitophagy promotes mitochondrial health and reduces ROS production to safeguard genomic integrity.
Interventions to combat genomic instability and aging. Genomic instability accelerates aging, and vice versa, ultimately leading to age-related diseases. Interestingly, all of these can be attenuated or reversed by systematic interventions, such as physical exercise, dietary restriction (DR), supplementation of nicotinamide riboside (NR), or NAD+, or even by direct correcting DNA repair genes or stimulating DNA repair pathways.