Senescence-Dependent MutSα Dysfunction Attenuates Mismatch Repair

Abstract

DNA damage and mutations in the genome increase with age. To determine the potential mechanisms of senescence-dependent increases in genomic instability, we analyzed DNA mismatch repair (MMR) efficiency in young and senescent human colonic fibroblast and human embryonic lung fibroblast. It was found that MMR activity is significantly reduced in senescent cells. Western blot and immunohistochemistry analysis revealed that hMSH2 and MSH6 protein (MutSA complex), which is a known key component in the MMR pathway, is markedly down-regulated in senescent cells. Moreover, the addition of purified MutSA to extracts from senescent cells led to the restoration of MMR activity. Semiquantitative reverse transcription-PCR analysis exhibited that MSH2 mRNA level is reduced in senescent cells. In addition, a decrease in E2F transcriptional activity in senescent cells was found to be crucial for MSH2 suppression. E2F1 small interfering RNA expression reduced hMSH2 expression and MMR activity in young human primary fibroblast cells. Importantly, expression of E2F1 in quiescent cells restored the MSH2 expression as well as MMR activity, whereas E2F1-infected senescent cells exhibited no restoration of MSH2 expression and MMR activity. These results indicate that the suppression of E2F1 transcriptional activity in senescent cells lead to stable repression of MSH2, followed by a induction of MutSA dysfunction, which results in a reduced cellular MMR capacity in senescent cells. (Mol Cancer Res 2008;6(6):978 -89)

Mismatch repair single nucleotide polymorphisms and thyroid cancer susceptibility

“…Also, in line with our results, rs1042821 has been associated with increased breast cancer risk in women of age >60 years and decreased risk in women of age ≤60 years (57). Finally, MSH6 has been demonstrated to be markedly downregulated in senescent cells (75), suggesting that MutSα activity decreases during the aging process. Since our results were based on stratified analysis, further studies are required to confirm this finding.…”

Regulation of E2Fs and senescence by PML nuclear bodies

“…In agreement with this, cells disabled for certain DNA repair genes senesce in culture due to their inability to repair the DNA damage triggered by endogenous metabolic processes (Cao et al 2003;Neri et al 2007;Zhang et al 2007;Chang et al 2008). Consistent with this idea, PML-expressing cells contained DNA damage foci labeled by anti-phospho-ATM (Fig.…”

Oxidation in the nucleotide pool, the DNA damage response and cellular senescence: Defective bricks build a defective house

“…MMR activity is also reported to be impaired in senescent cells, resulting from reduced mRNA levels of MSH2 and MSH6 [86]. The pivotal contribution of oxidized dNTPs towards mismatch repair-related DNA damage can be gauged from the fact that MTH1 overexpression reduces both baseline and oxidative stress-associated genomic 8-oxo-dG in MMR-deficient MEFs [87].…”

“…The pivotal contribution of oxidized dNTPs towards mismatch repair-related DNA damage can be gauged from the fact that MTH1 overexpression reduces both baseline and oxidative stress-associated genomic 8-oxo-dG in MMR-deficient MEFs [87]. Furthermore, significantly higher rates of microsatellite instability (MSI), a form of chromosomal abnormality, are reported in aging cells such as T lymphocytes [86,88] that undergo extensive cell division in vivo. MTH1 overexpression can rescue MSI in MSH6-deficient colorectal cancer cells [89], suggesting that improved sanitization of oxidized DNA precursors can prevent or inhibit the DNA strand breakage and aberrant repair intermediates that lead to senescence-associated DNA damage.…”