Role of mismatch repair in aging

Abstract

A common feature of aging is the accumulation of genetic damage throughout life. DNA damage can lead to genomic instability. Many diseases associated with premature aging are a result of increased accumulation of DNA damage. In order to minimize these damages, organisms have evolved a complex network of DNA repair mechanisms, including mismatch repair (MMR). In this review, we detail the effects of MMR on genomic instability and its role in aging emphasizing on the association between MMR and the other hallmarks of aging, serving to drive or amplify these mechanisms. These hallmarks include telomere attrition, epigenetic alterations, mitochondrial dysfunction, altered nutrient sensing and cell senescence. The close relationship between MMR and these markers may provide prevention and treatment strategies, to reduce the incidence of age-related diseases and promote the healthy aging of human beings.

The Many Ages of Microbiome–Gut–Brain Axis

“…The main cause of aging is usually considered the time-dependent increase in cellular damages [ 1 ]. Among others, the most considered biomarkers of aging in mammalians are DNA damage accumulation, apoptosis resistance, genomic instability, telomere shortening, epigenetic alterations, deregulated nutrient sensing, mitochondrial dysfunction, stem cell exhaustion, and altered intercellular communication [ 1 , 13 , 14 ]. The hallmarks of aging lead to both tissue function decrease and inflammation, in particular in the gastrointestinal system, increasing the predisposition to gut-associated diseases by causing alterations in the gut microbiome composition in elderly people [ 15 ].…”

Personalised neoantigen‐based therapy in colorectal cancer

“…The most important components of the MMR system are the MutS and MutL complexes (MSH2 and MSH6 form MutSα; MSH2 and MSH3 form MutSβ; MLH1 and PMS2 form MutLα; MLH1 and PMS1 form MutLβ; MLH1 and MLH3 form MutLγ). As MSH2 and MLH1 are proteins shared by MutS and MutL complexes, gene mutations will completely delay all MMR activities, resulting in the accumulation of insertion/deletion mutations in the repetitive nucleotide sequence regions of coding and non‐coding microsatellites 16–19 . Template and primer chains easily slip during replication, and this mismatch cannot be repaired in MMR defective cells.…”

Mismatch repair deficiency and clinical implications in prostate cancer

“…DNA MMR plays an important role in maintaining genomic fidelity during normal cell division 7 . The primary MMR proteins function as heterodimers (MSH2 binds to MSH6; MLH1 binds to PMS2) to repair base−base mismatches and insertion−deletion loops through a process of excision and DNA resynthesis 7 . The functional consequence of biallelic inactivation or epigenetic silencing of MMR genes—also termed MMRd—is the rapid accumulation of mutations throughout the genome.…”

“…DNA MMR plays an important role in maintaining genomic fidelity during normal cell division 7 . The primary MMR proteins function as heterodimers (MSH2 binds to MSH6; MLH1 binds to PMS2) to repair base−base mismatches and insertion−deletion loops through a process of excision and DNA resynthesis 7 .…”

“…7 The primary MMR proteins function as heterodimers (MSH2 binds to MSH6; MLH1 binds to PMS2) to repair base−base mismatches and insertion−deletion loops through a process of excision and DNA resynthesis. 7 The functional consequence of biallelic inactivation or epigenetic silencing of MMR genes -also termed MMRd-is the rapid accumulation of mutations throughout the genome. Microsatellite loci (i.e., short, tandem repeats of DNA sequences), which are particularly error prone during DNA replication, rapidly accumulate mutations and in turn MSI is the hallmark genomic features associated with MMRd.…”