DNA Damage

A DNA lesion creates an abnormal nucleotide or nucleotide fragment, causing a break in one or both chains of the DNA strand. ^[1] Genomic instability is defined as higher than normal rates of mutation within the genome. ^[2] Maintaining genomic stability relies on a coordinated network of cellular processes including DNA replication, DNA repair, and cell-cycle progression. ^[3]

The DNA damage response signaling pathway orchestrated by the ATM and ATR kinases is the central regulator that senses DNA damage and DNA replication stress. ^[3] Following induction of DNA damage, p53 is activated and upregulates p21, which triggers RB-E2F complex formation and cell cycle arrest. ^[4] Homologous recombination repairs DNA double-strand breaks by copying intact sequence information from a homologous template with high fidelity. ^[5] Endogenous DNA damage arises from cellular processes such as transcription and replication that can overwhelm high-fidelity DNA repair. ^[2]

The nuclear genome decays as organisms age, and the burden of several classes of DNA lesions is greater in older mammals than in young mammals. ^[6] The DNA damage theory of aging argues that genomic instability plays a causal role in aging, supported by progeroid syndromes in which inherited DNA repair defects accelerate aging. ^[6] DNA damage induces inflammation through activation of the cGAS-STING axis and NF-κB activation by ATM. ^[7] The accumulation of DNA damage contributes to aging by inducing cell death, senescence, and tissue dysfunction. ^{[7] [6]}

Defects in DNA repair and damage signaling render cancer cells vulnerable to DNA damage and reliant on their remaining repair and signaling activities. ^[8] A better understanding of the cellular response to DNA damage informs the classification and treatment of cancer. ^[9] Tumour radiosensitisation strategies exploit tumour-specific DNA repair deficiencies and signalling pathway addictions. ^[10]