Tissue-specific differences in the accumulation of sequence rearrangements with age

Wiktor-Brown, Dominika M.; Olipitz, Werner; Hendricks, Carrie A.; Rugo, Rebecca E.; Engelward, Bevin P.

doi:10.1016/j.dnarep.2008.01.012

Cited by 11 publications

(19 citation statements)

References 73 publications

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“…Interestingly, the frequency of spontaneous mitotic recombination was reported to increase in the pancreas, but not in the skin, of mice carrying a fluorescent reporter cassette (29). Spontaneous mitotic recombination is a rare event likely triggered by a spontaneous DSB.…”

Section: Discussionmentioning

confidence: 99%

Sirtuin 6 (SIRT6) rescues the decline of homologous recombination repair during replicative senescence

Mao

Tian

Meter

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

157

137

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Genomic instability is a hallmark of aging tissues. Genomic instability may arise from the inefficient or aberrant function of DNA double-stranded break (DSB) repair. DSBs are repaired by homologous recombination (HR) and nonhomologous DNA end joining (NHEJ). HR is a precise pathway, whereas NHEJ frequently leads to deletions or insertions at the repair site. Here, we used normal human fibroblasts with a chromosomally integrated HR reporter cassette to examine the changes in HR efficiency as cells progress to replicative senescence. We show that HR declines sharply with increasing replicative age, with an up to 38-fold decrease in efficiency in presenescent cells relative to young cells. This decline is not explained by a reduction of the number of cells in S/G 2 /M stage as presenescent cells are actively dividing. Expression of proteins involved in HR such as Rad51, Rad51C, Rad52, NBS1, and Sirtuin 6 (SIRT6) diminished with cellular senescence. Supplementation of Rad51, Rad51C, Rad52, and NBS1 proteins, either individually or in combination, did not rescue the senescence-related decline of HR. However, overexpression of SIRT6 in "middle-aged" and presenescent cells strongly stimulated HR repair, and this effect was dependent on mono-ADP ribosylation activity of poly(ADP-ribose) polymerase (PARP1). These results suggest that in aging cells, the precise HR pathway becomes repressed giving way to a more error-prone NHEJ pathway. These changes in the processing of DSBs may contribute to age-related genomic instability and a higher incidence of cancer with age. SIRT6 activation provides a potential therapeutic strategy to prevent the decline in genome maintenance.A ging is associated with an increased mutation rate (1) and the appearance of genomic rearrangements (2). The accumulation of mutations and rearrangements is a contributing cause of aging and leads to a decline of tissue functionality and an increased incidence of tumors. These mutations and genomic rearrangements arise from aberrant repair of DNA doublestranded breaks (DSBs).DSBs are dangerous DNA lesions. If left unrepaired or repaired incorrectly, DSBs result in a massive loss of genetic information, chromosomal aberrations, or cell death. DSBs are repaired by two major pathways: nonhomologous end joining (NHEJ) and homologous recombination (HR) (3). NHEJ modifies the broken DNA ends and ligates them together with no requirement for homology, often generating deletions or insertions (4). In contrast, HR uses an undamaged DNA template to repair the break, leading to the reconstitution of the original sequence (5). HR repair is responsible for approximately one quarter of DNA repair events and has much slower repair kinetics than NHEJ (6). HR repair begins with the MRE11, NBS1, and Rad50 complex binding to DNA ends and mediating end resection. The RPA protein is then recruited to DNA ends, in a process regulated by CtIP (7). Once the ends are resected, Rad51 forms nucleoprotein filaments and mediates strand invasion of the filament into duplex DNA, usual...

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Section: Discussionmentioning

confidence: 99%

Sirtuin 6 (SIRT6) rescues the decline of homologous recombination repair during replicative senescence

Mao

Tian

Meter

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

157

137

View full text Add to dashboard Cite

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“…Wiktor-Brown et al [19] investigated the effects of aging on the frequency of HR events in the FYDR mice. In pancreas, 23-fold increase in recombinant cell frequency with age was noted in vivo .…”

Section: Figurementioning

confidence: 99%

“…Recent work has begun addressing the potential role of endogenous/background DNA damage in background mutagenesis [5, 6, 8, 16-19]. The Engelward laboratory developed a sensitive mouse model in which HR events at an integrated Fluorescent Yellow Direct Repeat (FYDR) transgene give rise to a fluorescent signal.…”

Section: Introductionmentioning

confidence: 99%

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Contributions of DNA repair and damage response pathways to the non-linear genotoxic responses of alkylating agents

Klapacz

Pottenger

Engelward

et al. 2016

Mutation Research/Reviews in Mutation Research

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From a risk assessment perspective, DNA-reactive agents are conventionally assumed to have genotoxic risks at all exposure levels, thus applying a linear extrapolation for low-dose responses. New approaches discussed here, including more diverse and sensitive methods for assessing DNA damage and DNA repair, strongly support the existence of measurable regions where genotoxic responses with increasing doses are insignificant relative to control. Model monofunctional alkylating agents have in vitro and in vivo datasets amenable to determination of points of departure (PoDs) for genotoxic effects. A session at the 2013 Society of Toxicology meeting provided an opportunity to survey the progress in understanding the biological basis of empirically-observed PoDs for DNA alkylating agents. Together with the literature published since, this review discusses cellular pathways activated by endogenous and exogenous alkylation DNA damage. Cells have evolved conserved processes that monitor and counteract a spontaneous steady-state level of DNA damage. The ubiquitous network of DNA repair pathways serves as the first line of defense for clearing of the DNA damage and preventing mutation. Other biological pathways discussed here that are activated by genotoxic stress include post-translational activation of cell cycle networks and transcriptional networks for apoptosis/cell death. The interactions of various DNA repair and DNA damage response pathways provide biological bases for the observed PoD behaviors seen with genotoxic compounds. Thus, after formation of DNA adducts, the activation of cellular pathways can lead to the avoidance a mutagenic outcome. The understanding of the cellular mechanisms acting within the low-dose region will serve to better characterize risks from exposures to DNA-reactive agents at environmentally-relevant concentrations.

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“…Sequence rearrangements promoted by homologous recombination (HR) can restore full-length coding sequence and thus give rise to a fluorescent signal (15). FYDR mice demonstrate an age-related increase in HR in the pancreas, and embryonic stem cells harboring analogous transgenes show HR in response to chemotherapeutic alkalating agents (16, 17). In the present studies, we measured the effect of thoracic ionizing radiation on HR in the FYDR mouse esophagus compared to the pancreas and femoral bone marrow.…”

Section: Introductionmentioning

confidence: 99%

Irradiated Esophageal Cells are Protected from Radiation-Induced Recombination by MnSOD Gene Therapy

et al. 2010

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Radiation-induced DNA damage is a precursor to mutagenesis and cytotoxicity. During radiotherapy, exposure of healthy tissues can lead to severe side effects. We explored the potential of mitochondrial SOD (MnSOD) gene therapy to protect esophageal, pancreatic and bone marrow cells from radiation-induced genomic instability. Specifically, we measured the frequency of homologous recombination (HR) at an integrated transgene in the Fluorescent Yellow Direct Repeat (FYDR) mice, in which an HR event can give rise to a fluorescent signal. Mitochondrial SOD plasmid/liposome complex (MnSOD-PL) was administered to esophageal cells 24 h prior to 29 Gy upper-body irradiation. Single cell suspensions from FYDR, positive control FYDR-REC, and negative control C57BL/6NHsd (wild-type) mouse esophagus, pancreas and bone marrow were evaluated by flow cytometry. Radiation induced a statistically significant increase in HR 7 days after irradiation compared to unirradiated FYDR mice. MnSOD-PL significantly reduced the induction of HR by radiation at day 7 and also reduced the level of HR in the pancreas. Irradiation of the femur and tibial marrow with 8 Gy also induced a significant increase in HR at 7 days. Radioprotection by intraesophageal administration of MnSOD-PL was correlated with a reduced level of radiation-induced HR in esophageal cells. These results demonstrate the efficacy of MnSOD-PL for suppressing radiation-induced HR in vivo.

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Tissue-specific differences in the accumulation of sequence rearrangements with age

Cited by 11 publications

References 73 publications

Sirtuin 6 (SIRT6) rescues the decline of homologous recombination repair during replicative senescence

Sirtuin 6 (SIRT6) rescues the decline of homologous recombination repair during replicative senescence

Contributions of DNA repair and damage response pathways to the non-linear genotoxic responses of alkylating agents

Irradiated Esophageal Cells are Protected from Radiation-Induced Recombination by MnSOD Gene Therapy

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