DNA damage may causally contribute to aging, as exemplified by the premature appearance of multiple symptoms of aging in a growing family of human syndromes and in mice with genetic defects in genome maintenance transduction pathways.
Organisms have developed several DNA repair signaling transduction pathways as well as DNA damage checkpoints to cope with the frequent challenge of endogenous and exogenous DNA insults.
Functional consequences associated with impaired DNA repair include embryonic lethality, shortened life span, rapid ageing, impaired growth, and a variety of syndromes, including a pronounced manifestation of cancer.
The wide diversity of DNA-lesion types necessitates multiple, largely distinct DNA-repair mechanisms. While some lesions are subject to direct protein-mediated reversal, most are repaired by a sequence of catalytic events mediated by multiple proteins.
In mismatch repair (MMR), detection of mismatches and insertion/deletion loops triggers a single-strand incision that is then acted upon by nuclease, polymerase and ligase enzymes.
In base-excision repair (BER), a damaged base is often recognized by a DNA glycosylase enzyme that mediates base removal before nuclease, polymerase and ligase proteins complete the repair in processes overlapping with those used in single-strand break repair (SSBR).
The nucleotide excision repair (NER) system, which recognizes helix-distorting base lesions, operates via two sub-pathways that differ in the mechanism of lesion recognition: transcription-coupled NER, which specifically targets lesions that block transcription, and global-genome NER.
The mechanisms of DNA damage checkpoints are best understood during their responses to double-strand breaks (DSBs). Initiation of these checkpoints is dependent on the transient recruitment of the MRE11/RAD50/NBS1 (MRN) complex at DSB sites, followed by the recruitment/activation of ataxia–telangiectasia mutated (ATM) a member of the family of phosphoinositide-3-kinase-related kinases (PIKKs).
In addition, two other PIKKs, DNA-dependent protein kinase (DNA–PK) and ATR (ATM and Rad3 related), are also activated and involved in the response to DSBs.
ATM, ATR, and DNA–PK phosphorylate various targets that contribute to the overall DNA damage response. Therefore, within minutes of DSB formation, active ATM phosphorylates different proteins that are essential for DNA-damage response and repair.
1. Hakem, R. (2008). DNA‐damage repair; the good, the bad, and the ugly. The EMBO journal, 27(4), 589-605.
2. Jackson, S. P., & Bartek, J. (2009). The DNA-damage response in human biology and disease. Nature, 461(7267), 1071.