The role of DNA exonucleases in protecting genome stability and their impact on ageing

Mason, Penelope A.; Cox, Lynne S.

doi:10.1007/s11357-011-9306-5

Cited by 32 publications

(27 citation statements)

References 215 publications

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“…We now know a great deal more about how DNA is repaired and damaged proteins are removed, and how failures in these repair and removal systems can contribute to pathology and perhaps even to the process of aging. 3,[127][128][129] This nicely illustrates the point that antioxidant defenses are not completely effective in preventing oxidative damage in vivo. Perhaps they simply cannot be totally effective (e.g., it is impossible to evolve an effective scavenger of OH • in vivo, for reasons discussed elsewhere 3,83 ), or perhaps they are evolved to be so because H2O2 (and maybe some other species) play useful roles in vivo, as discussed above.…”

Section: Antioxidant Defensesmentioning

confidence: 90%

Free radicals and antioxidants: updating a personal view

2012

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This article looks back to the antioxidant/free radical field in 1994 and discusses how it has progressed in the past 18 years. In some areas, there has been little change: the role of oxygen radicals and other reactive oxygen species (ROS) in the origin or progression of most human diseases remains uncertain, with cancer and neurodegenerative disease being likely exceptions. Even in diseases in which ROS are involved there has been little progress in developing effective antioxidant treatments. Mega-doses of dietary antioxidants have also generally failed to prevent human disease, in part because they do not decrease oxidative damage in vivo (as revealed by robust biomarkers). However, some strategies that are known to delay disease onset may act, at least in part, by decreasing oxidative damage levels. Nevertheless, far more is known today about endogenous antioxidant defenses and how they are regulated, which has led to a deeper understanding of how some ROS can act as signaling molecules. Increasing endogenous antioxidant levels (e.g., by supplying "pro-oxidants") may be a better approach to therapeutics and disease prevention than consuming large doses of "dietary antioxidants."

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Section: Antioxidant Defensesmentioning

confidence: 90%

Free radicals and antioxidants: updating a personal view

2012

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“…In addition to immunity‐related genes, we observed a consistent downregulation of Exonuclease 1 ( Exo1 ) in birds selected for increased reproductive investment. Exo1 encodes a protein that plays an essential role in DNA repair mechanisms and the maintenance of genome stability (Mason and Cox 2012), and increased Exo1 expression has been linked to longevity in humans (Nebel et al. 2009).…”

Section: Discussionmentioning

confidence: 99%

Artificial selection reveals the role of transcriptional constraints in the maintenance of life history variation

et al. 2020

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The trade‐off between reproduction and self‐maintenance is a cornerstone of life history theory, yet its proximate underpinnings are elusive. Here, we used an artificial selection approach to create replicated lines of Japanese quail (Coturnix japonica) that differ genetically in their reproductive investment. Whole transcriptome sequencing revealed that females from lines selected for high reproductive output show a consistent upregulation of genes associated with reproduction but a simultaneous downregulation of immune genes. Concordant phenotypic differences in immune function (i.e., specific antibody response against keyhole limpet hemocyanin) were observed between the selection lines, even in males who do not provide parental care. Our findings demonstrate the key role of obligate transcriptional constraints in the maintenance of life history variation. These constraints set fundamental limits to productivity and health in natural and domestic animal populations.

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“…11,40–44 We observed levels of free Hb-α, ROS and Nrf2 to be indifferent between the active colitides, as is the reported incidence and prevalence of CRC in these patients. 13,37–41,45, The development of CRC in IBD patients therefore, may not be influenced by disease activity and the extent or duration of disease alone, but by hypersensitivity to ROS, which may partly explain the identical incidence and prevalence of CRC complicating the two pathologies. 12,44,46,47 In reference to the published cumulative risk data reported that patients with IBD who were followed and treated for a long time period who developed CRC before or after colectomy surgery had the prior disease for not less than 8–10 years.…”

Section: Discussionmentioning

confidence: 99%

Implications of the Colonic Deposition of Free Hemoglobin-α Chain

Myers

Schaffer

Korolkova

et al. 2014

Inflammatory Bowel Diseases

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Purpose We analyzed inflamed mucosal/submucosal layers of ulcerative colitis (UC=63) and Crohn’s colitis (CC=50) and unexpectedly we unveiled a pool of free-hemoglobin-alpha (Hb-α) chain. Patients with colitides have increased ROS, DNA-oxidation products, free-iron in mucosa, in pre-neoplastic, and in colitis-cancers and increased risks of developing colorectal-cancer (CRC). All IBD-related-CRC lesions are found in segments with colitis. Linking this information we investigated whether free-Hb-α is key transformational stepping that increases colitis-related-CRC vulnerability. Methods UC/CC samples were profiled using MALDI-MS; protein identification was made by LCM. Diverticulitis (DV) was used as control (Ctrl). The presence of Hb(n) (n=α, β and hemin)/Hb was validated by Western blotting (WB) and immunohistochemistry (IHC). We tested for DNA-damage (DNAD) by exposing normal colonic-epithelial-cell-line, NCM460, to 10μM and 100μM of Hb(n)/Hb, individually for 2 h, 6 h, and 12 h. Quantification of Hb-α-staining was done by Nikon Elements Advance Research Analysis software. ROS was measured by the production of 8-OHdG. DNAD was assessed by Comet-assay. Colonic tissue homogenate antioxidants Nrf2-, CAT-, SOD- and GPx-expressions was analyzed densitometrically/ normalized by β-actin. Results IHC of CC/UC mucosal/submucosal-compartments stained strongly positive for Hb-α and significantly higher vs. Ctrl. NCM460 exposed to Hb(n)/Hb exhibited steadily-increasing ROS and subsequent DNAD. DNAD was higher in 10μM than 100μM in Hb-β/hemin the first 2 h then plateaued followed by DNAD-repair. This may be likely due to apoptosis in the later concentration. Nrf2 enzyme activities among UC, CC and UCAC were observed impaired in all IBD subjects. Decreased levels of Nrf2 among UC vs. CC patients with active disease was insignificant as well as vs. Ctrls but significantly lower in UCAC vs. Ctrl. SOD was decreased in UC and UCAC and GPx in CC but statistically not significant. Comparing CC vs. UC, SOD was significantly lower in CC (p< 0.05). CAT was observed increased among CC/UC/UCAC patients and GPx in UC and UCAC vs. Ctrl, respectively, and significantly increased in CC vs. Ctrl (p< 0.01) Conclusion In the colitides mucosal/submucosal tissue microenvironments demonstrated pool of free-Hb-α-chain. In vitro exposure of NCM460-cells to Hb(n)/Hb induced ROS and DNAD. Toxic effect of free-Hb-α, in colonic epithelial cells is therefore through production of ROS-formation modulated by impairment of antioxidant effects. Targeting reduction-oxidation-sensitive pathways and transcription factors may offer options for IBD-management and colitis-related-cancer prevention.

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The role of DNA exonucleases in protecting genome stability and their impact on ageing

Cited by 32 publications

References 215 publications

Free radicals and antioxidants: updating a personal view

Free radicals and antioxidants: updating a personal view

Artificial selection reveals the role of transcriptional constraints in the maintenance of life history variation

Implications of the Colonic Deposition of Free Hemoglobin-α Chain

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