Caloric restriction promotes genomic stability by induction of base excision repair and reversal of its age-related decline

Cabelof, Diane C.; Yanamadala, Sunitha; Raffoul, Julian J.; Guo, ZhongMao; Soofi, Abdulsalam; Heydari, Ahmad R.

doi:10.1016/s1568-7864(02)00219-7

Cited by 115 publications

(94 citation statements)

References 40 publications

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“…It has been clearly demonstrated and widely accepted that ␤-pol is the rate-limiting enzyme in MFG-BER (22). Our laboratory has also demonstrated that ␤-pol expression and activity strongly correlate with MFG-BER under a variety of environmental stimuli (52,53,58,59). A recent study (37) examining kinetic data of various BER enzymes has also suggested that ␤-polmediated MFG-BER may be the predominant BER pathway in vivo.…”

Section: Discussionmentioning

confidence: 67%

Apurinic/Apyrimidinic Endonuclease (APE/REF-1) Haploinsufficient Mice Display Tissue-specific Differences in DNA Polymerase β-Dependent Base Excision Repair

Raffoul

Cabelof

Nakamura

et al. 2004

Journal of Biological Chemistry

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Apurinic/apyrimidinic (AP) endonuclease (APE) is a multifunctional protein possessing both DNA repair and redox regulatory activities. In base excision repair (BER), APE is responsible for processing spontaneous, chemical, or monofunctional DNA glycosylase-initiated AP sites via its 5 -endonuclease activity and 3 -"endtrimming" activity when processing residues produced as a consequence of bifunctional DNA glycosylases. In this study, we have fully characterized a mammalian model of APE haploinsufficiency by using a mouse containing a heterozygous gene-targeted deletion of the APE gene (Apex ؉/؊ ). Our data indicate that Apex ؉/؊ mice are indeed APE-haploinsufficient, as exhibited by a 40 -50% reduction (p < 0.05) in APE mRNA, protein, and 5 -endonuclease activity in all tissues studied. Based on gene dosage, we expected to see a concomitant reduction in BER activity; however, by using an in vitro G:U mismatch BER assay, we observed tissue-specific alterations in monofunctional glycosylase-initiated BER activity, e.g. liver (35% decrease, p < 0.05), testes (55% increase, p < 0.05), and brain (no significant difference). The observed changes in BER activity correlated tightly with changes in DNA polymerase ␤ and AP site DNA binding levels. We propose a mechanism of BER that may be influenced by the redox regulatory activity of APE, and we suggest that reduced APE may render a cell/tissue more susceptible to dysregulation of the polymerase ␤-dependent BER response to cellular stress.Apurinic/apyrimidinic (AP) 1 endonuclease (APE) is a multifunctional protein involved in the maintenance of genomic integrity and in the regulation of gene expression. After the initial discovery in Escherichia coli (1), APE was purified from calf thymus DNA and extensively characterized as an endonuclease that cleaves the backbone of double-stranded DNA containing AP sites (2, 3). APE homologues were subsequently identified and characterized in many organisms, including yeast as APN1 (4), mice as Apex (5, 6), and humans as HAP1 (7). In addition to its major 5Ј-endonuclease activity, APE also expresses minor 3Ј-phosphodiesterase, 3Ј-phosphatase, and 3Ј 3 5Ј-exonuclease activities (8), the biological significance of which is controversial (9). Independent of its discovery as a DNA repair protein, APE was also characterized as REF-1, for redox factor-1, a redox activator of cellular transcription factors (10 -12). Although the molecular detail of APE redox activity is still unclear (13), the discovery of APE as a regulator of transcriptional activity may underscore the importance of its involvement in cellular stress-response pathways.APE is the primary enzyme responsible for recognition and incision of non-coding AP sites in DNA arising as a consequence of spontaneous, chemical, or DNA glycosylase-mediated hydrolysis of the N-glycosyl bond initiated by the base excision repair (BER) pathway. These lesions are particularly common, arising at the rate of ϳ50,000 -200,000 AP sites per cell per day under normal physiological conditions (14,...

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Section: Discussionmentioning

confidence: 67%

Apurinic/Apyrimidinic Endonuclease (APE/REF-1) Haploinsufficient Mice Display Tissue-specific Differences in DNA Polymerase β-Dependent Base Excision Repair

Raffoul

Cabelof

Nakamura

et al. 2004

Journal of Biological Chemistry

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“…This protection occurs via two series of mechanisms. The first encompasses activation of DNA repair (Cabelof et al 2003), ROS detoxification machinery (Xia et al 1995), and increased fidelity of DNA replication (Srivastava et al 1993). The second comprises direct modulation of chromatin structure, which has positive effects on DNA recombination, DNA replication, and cell cycle progression, among other processes (Vaquero 2009).…”

Section: The Skinny On Cr and Chromatinmentioning

confidence: 99%

“…CR increases DNA repair activity and reverses the decreased levels of such activity observed in aged mice (Heydari et al 2007). The DNA repair pathways up-regulated by CR are the three main mechanisms involving ssDNA, NER (nucleotide excision repair) (Guo et al 1998), BER (base excision repair) (Cabelof et al 2003), S-phase-dependent mismatch repair (Tsao et al 2002), and the most common form of DSB repair, NHEJ (nonhomologous end joining) (Um et al 2003). Interestingly, CR not only increases expression of the DNA repair machinery (Heydari et al 2007), but also amplifies the activity and fidelity of critical enzymes such as DNA polymerases a and b (Cabelof et al 2003).…”

Section: Ros and Chromatinmentioning

confidence: 99%

Calorie restriction and the exercise of chromatin

Vaquero¹,

Reinberg²

2009

Genes Dev.

137

140

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Since the earliest stages of evolution, organisms have faced the challenge of sensing and adapting to environmental changes for their survival under compromising conditions such as food depletion or stress. Implicit in these responses are mechanisms developed during evolution that include the targeting of chromatin to allow or prevent expression of fundamental genes and to protect genome integrity. Among the different approaches to study these mechanisms, the analysis of the response to a moderate reduction of energy intake, also known as calorie restriction (CR), has become one of the best sources of information regarding the factors and pathways involved in metabolic adaptation from lower to higher eukaryotes. Furthermore, responses to CR are involved in life span regulation—conserved from yeast to mammals—and therefore have garnered major research interest. Herein we review current knowledge of responses to CR at the molecular level and their functional link to chromatin.

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“…While there is evidence that DNA BER is upregulated concomitantly with increased longevity in mice (e.g., Cabelof et al 2003b;Stuart et al 2004;Kisby et al 2010), other results question the relationship between BER and longevity. For example, ∼50% reduction in either APE or polβ activity is not associated with reduced lifespan in unstressed mice (Meira et al 2001;Cabelof et al 2006).…”

Section: Introductionmentioning

confidence: 99%

Activities of DNA base excision repair enzymes in liver and brain correlate with body mass, but not lifespan

Page

Stuart

2011

AGE

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Accumulation of DNA lesions compromises replication and transcription and is thus toxic to cells. DNA repair deficiencies are generally associated with cellular replicative senescence and premature aging syndromes, suggesting that efficient DNA repair is required for normal longevity. It follows that the evolution of increasing lifespan amongst animal species should be associated with enhanced DNA repair capacities. Although UV damage repair has been shown to correlate positively with mammalian species lifespan, we lack similar insight into many other DNA repair pathways, including base excision repair (BER). DNA is continuously exposed to reactive oxygen species produced during aerobic metabolism, resulting in the occurrence of oxidative damage within DNA. Shortpatch BER plays an important role in repairing the resultant oxidative lesions. We therefore tested whether an enhancement of BER enzyme activities has occurred concomitantly with the evolution of increased maximum lifespan (MLSP). We collected brain and liver tissue from 15 vertebrate endotherm species ranging in MLSP over an order of magnitude. We measured apurinic/ apyrimidinic (AP) endonuclease activity, as well as the rates of nucleotide incorporation into an oligonucleotide containing a single nucleotide gap (catalyzed by BER polymerase β) and subsequent ligation of the oligonucleotide. None of these activities correlated positively with species MLSP. Rather, nucleotide incorporation and oligonucleotide ligation activities appeared to be primarily (and negatively) correlated with species body mass.

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Caloric restriction promotes genomic stability by induction of base excision repair and reversal of its age-related decline

Cited by 115 publications

References 40 publications

Apurinic/Apyrimidinic Endonuclease (APE/REF-1) Haploinsufficient Mice Display Tissue-specific Differences in DNA Polymerase β-Dependent Base Excision Repair

Apurinic/Apyrimidinic Endonuclease (APE/REF-1) Haploinsufficient Mice Display Tissue-specific Differences in DNA Polymerase β-Dependent Base Excision Repair

Calorie restriction and the exercise of chromatin

Activities of DNA base excision repair enzymes in liver and brain correlate with body mass, but not lifespan

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