Repair and Genetic Consequences of Endogenous DNA Base Damage in Mammalian Cells

Barnes, Deborah E.; Lindahl, Tomas

doi:10.1146/annurev.genet.38.072902.092448

Cited by 686 publications

(557 citation statements)

References 146 publications

(144 reference statements)

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“…The BER machinery appears to have evolved primarily to catalyze the removal of oxidative and alkylation base damage. 8,9 Short patch base excision repair is initiated when the damaged base is recognized and excised by a DNA glycosylase, leaving an abasic site, as shown in Figure 1. 8 Apurinic/ apyrimidinic (AP) endonuclease 1 (APE1) then incises the DNA backbone 5' to the abasic site, leaving a 3'-OH and a 5'-deoxyribosephosphate (dRP) group.…”

Section: Dna Damage and Base Excision Repairmentioning

confidence: 99%

“…DNA damage removed by DNA glycosylases include uracil and bases damaged by oxidation and alkylation (reviewed in ref. 9).…”

Section: Germline and Tumor-associated Variants Of Dna Glycosylases Mmentioning

confidence: 99%

“…Uracil arises in DNA by direct incorporation by replicative DNA polymerases and through the deamination of cytosine. 8,9 In mammals, there are two uracil DNA glycosylases, UNG and SMUG1. Transcription of the UNG gene from different promoters results in the synthesis of both the nuclear www.landesbioscience.com…”

Section: Germline and Tumor-associated Variants Of Dna Glycosylases Mmentioning

confidence: 99%

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Is Base Excision Repair a Tumor Suppressor Mechanism?

Sweasy¹,

Lang²,

DiMaio³

2006

Cell Cycle

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The base excision repair pathway is critical for the removal of oxidized and methylated bases from the DNA. Much of this DNA damage arises endogenously, as a result of oxygen metabolism. Several proteins including DNA glycosylases, the APE1 endonuclease, DNA polymerase β and DNA ligase, act in a highly regulated and coordinated manner during base excision repair to excise the base adducts from the DNA and restore the normal DNA sequence. Both germline and tumor-associated variants of genes encoding these proteins have been identified in humans. In many cases, the protein variant has been shown to have properties that could contribute to the development of cancer, suggesting that base excision repair acts as a tumor suppressor mechanism in humans. Limited epidemiological studies are consistent with this view. Our review of the literature indicates that additional laboratory and epidemiological studies of the role of base excision repair in cancer etiology is warranted.

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Section: Dna Damage and Base Excision Repairmentioning

confidence: 99%

“…DNA damage removed by DNA glycosylases include uracil and bases damaged by oxidation and alkylation (reviewed in ref. 9).…”

Section: Germline and Tumor-associated Variants Of Dna Glycosylases Mmentioning

confidence: 99%

Section: Germline and Tumor-associated Variants Of Dna Glycosylases Mmentioning

confidence: 99%

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Is Base Excision Repair a Tumor Suppressor Mechanism?

Sweasy¹,

Lang²,

DiMaio³

2006

Cell Cycle

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“…The accumulation of DNA damage, however, may be the most detrimental to cell viability due to the risk that replication and transcription of the genome will be permanently compromised. The exposure of mammalian DNA to endogenous genotoxic agents has been estimated to account for on the order of 10,000 DNA lesions per cell per day (Lindahl 1993), including base loss or modification and strand breaks (Barnes and Lindahl 2004). The failure to properly remove and repair DNA lesions can result in genomic instability, mutagenesis, transcriptional blockage, and/ or apoptotic cell death.…”

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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“…The mutagenic properties of DNA damage are important in mitotic cells where they give rise to mutations. 8 The cytotoxic lesions are more relevant to aging and functional decline in postmitotic tissues where DNA damage does not give rise to mutations through cell division. Instead the damage may persist and cause constitutive problems e.g., with transcription.…”

Section: Oxidative Dna Damage and Aging In C Elegansmentioning

confidence: 99%

Active transcriptomic and proteomic reprogramming in theC. elegansnucleotide excision repair mutant xpa-1

Kassahun

Nilsen

2013

Worm

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O xidative stress promotes human aging and contributes to common neurodegenerative diseases. Endogenous DNA damage induced by oxidative stress is believed to be an important promoter of neurodegenerative diseases. Although a large amount of evidence correlates a reduced DNA repair capacity with aging and neurodegenerative disease, there is little direct evidence of causality. Moreover, the contribution of oxidative DNA damage to the aging process is poorly understood. We have used the nematode Caenorhabditis elegans to study the contribution of oxidative DNA damage and repair to aging. C. elegans is particularly well suited to tackle this problem because it has a minimum complexity DNA repair system, which enables us to circumvent the important limitation presented by the extensive redundancy of DNA repair enzymes in mammals. Oxidative DNA Damage and Aging in C. elegansThe free radical theory of aging is an example of a hypothesis that, because it intuitively makes sense, is attractive both to scientists and to the general public. The theory has been enormously influential and has inspired scientists to test its implications ever since its first formulation by Denham Harman. 1 As such it is a good theory because it suggests many testable hypotheses. However, few experiments have provided direct support of the original theory. This has led to the formulation of many offshoots like the mitochondrial theory of aging and the stochastic damage accumulation theory of aging.One prediction that can be made from all of these theories is that oxidative damage to cellular macromolecules contributes to the progressive loss of function associated with aging. As DNA, unlike other cellular macromolecules, cannot be replaced in its entirety, it seems logical that maintenance of genomic stability would promote longevity and limit functional loss during aging.A role for passive and stochastic accumulation of oxidative DNA damage in aging is often dismissed by scientists outside the DNA repair field for three principal reasons; first, even though levels of reactive oxygen species (ROS) increase with age 2,3 and DNA repair capacity diminishes with age, 4 it has been difficult to unequivocally show that oxidative DNA damage accumulates with age. Also, since a plethora of different types of DNA lesions are induced by ROS, it is not entirely clear which types of lesions are more relevant to the aging phenotype. Second, there is no good correlation between mutation accumulation and aging. [5][6][7] Third, mutants that fail to repair oxidative DNA damage show normal lifespan. However, there are technical and biological factors that would explain these observations and further research is needed to determine whether and how oxidative DNA damage contributes to aging. Segmental Progeroid NER SyndromesIt is often overlooked that DNA damage may not only be mutagenic, but also

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Repair and Genetic Consequences of Endogenous DNA Base Damage in Mammalian Cells

Cited by 686 publications

References 146 publications

Is Base Excision Repair a Tumor Suppressor Mechanism?

Is Base Excision Repair a Tumor Suppressor Mechanism?

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

Active transcriptomic and proteomic reprogramming in theC. elegansnucleotide excision repair mutant xpa-1

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