Regulation of DNA glycosylases and their role in limiting disease

Sampath, Harini; McCullough, Amanda K.; Lloyd, R. Stephen

doi:10.3109/10715762.2012.655730

Cited by 43 publications

(50 citation statements)

References 233 publications

(345 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We now appreciate that there exist a collection of conserved DNA glycosylases that exhibit specificity for a broad range of substrate bases, including the deamination product of cytosine, uracil, the alkylation product 3-methyladenine, and the oxidation product 8-oxoguanine, to name a few (16,177). Piecing together the information at the time, it was clear that organisms had evolved a DNA repair pathway which (i) excised a modified substrate base by breaking the N-glycosylic bond, (ii) cleaved the DNA backbone 5¢ to the resulting AP site (class II incision), (iii) removed the 5¢-abasic fragment via some form of nuclease degradation, (iv) carried out repair replication, and (v) sealed the remaining nick via DNA ligation.…”

Section: Introductionmentioning

confidence: 99%

Human Apurinic/Apyrimidinic Endonuclease 1

2014

Antioxidants & Redox Signaling

229

221

View full text Add to dashboard Cite

Significance: Human apurinic/apyrimidinic endonuclease 1 (APE1, also known as REF-1) was isolated based on its ability to cleave at AP sites in DNA or activate the DNA binding activity of certain transcription factors. We review herein topics related to this multi-functional DNA repair and stress-response protein. Recent Advances: APE1 displays homology to Escherichia coli exonuclease III and is a member of the divalent metal-dependent a/b fold-containing phosphoesterase superfamily of enzymes. APE1 has acquired distinct active site and loop elements that dictate substrate selectivity, and a unique N-terminus which at minimum imparts nuclear targeting and interaction specificity. Additional activities ascribed to APE1 include 3¢-5¢ exonuclease, 3¢-repair diesterase, nucleotide incision repair, damaged or site-specific RNA cleavage, and multiple transcription regulatory roles. Critical Issues: APE1 is essential for mouse embryogenesis and contributes to cell viability in a genetic background-dependent manner. Haploinsufficient APE1 +/ -mice exhibit reduced survival, increased cancer formation, and cellular/tissue hyper-sensitivity to oxidative stress, supporting the notion that impaired APE1 function associates with disease susceptibility. Although abnormal APE1 expression/localization has been seen in cancer and neuropathologies, and impaired-function variants have been described, a causal link between an APE1 defect and human disease remains elusive. Future Directions: Ongoing efforts aim at delineating the biological role(s) of the different APE1 activities, as well as the regulatory mechanisms for its intra-cellular distribution and participation in diverse molecular pathways. The determination of whether APE1 defects contribute to human disease, particularly pathologies that involve oxidative stress, and whether APE1 small-molecule regulators have clinical utility, is central to future investigations. Antioxid. Redox Signal. 20,

show abstract

Section: Introductionmentioning

confidence: 99%

Human Apurinic/Apyrimidinic Endonuclease 1

2014

Antioxidants & Redox Signaling

229

221

View full text Add to dashboard Cite

show abstract

“…A brief overview of structure and function of each of these glycosylases is presented below. For more detailed insights into tissue specificities and regulation of these glycosylases, the reader is directed to a recent review [Sampath et al, 2012a]. Mouse models of other BER glycosylases, including the alkyladenine DNA glycosylase (AAG) and uracil DNA glycosylase have also been studied extensively with respect to various pathologies such as cancer and neurodegeneration.…”

Section: Introductionmentioning

confidence: 99%

Oxidative DNA damage in disease—Insights gained from base excision repair glycosylase‐deficient mouse models

Sampath

2014

Environ and Mol Mutagen

Self Cite

View full text Add to dashboard Cite

Cellular components, including nucleic acids, are subject to oxidative damage. If left unrepaired, this damage can lead to multiple adverse cellular outcomes, including increased mutagenesis and cell death. The major pathway for repair of oxidative base lesions is the base excision repair pathway, catalyzed by DNA glycosylases with overlapping but distinct substrate specificities. To understand the role of these glycosylases in the initiation and progression of disease, several transgenic mouse models have been generated to carry a targeted deletion or overexpression of one or more glycosylases. This review summarizes some of the major findings from transgenic animal models of altered DNA glycosylase expression, especially as they relate to pathologies ranging from metabolic disease and cancer to inflammation and neuronal health. Environ. Mol. Mutagen. 55:689-703, 2014. V C 2014 Wiley Periodicals, Inc.

show abstract

“…A consistent picture of the transcriptional regulation of the DNA repair enzymes has yet to be determined (for a review see [58]). The promoters of the housekeeping glycosylases, OGG1 and NTH1 have been cloned and analyzed and BRCA1 has been shown to stimulate the expression of both enzymes [59] (and for a review see [60]).…”

Section: Base Excision Repair In Eukaryotic Cellsmentioning

confidence: 99%

“…The BER glycosylases are also differentially regulated during the cell cycle [58]. In the case of the monofunctional enzymes, UNG2 is upregulated in S phase, repairs postreplicative U opposite A, and interacts with PCNA (which likely is required given its postreplication duty).…”

Section: Base Excision Repair In Eukaryotic Cellsmentioning

confidence: 99%

Base excision repair: A critical player in many games

2014

View full text Add to dashboard Cite

This perspective reviews the many dimensions of base excision repair from a 10,000 foot vantage point and provides one person’s view on where the field is headed. Enzyme function is considered under the lens of X-ray diffraction and single molecule studies. Base excision repair in chromatin and telomeres, regulation of expression and the role of posttranslational modifications are also discussed in the context of enzyme activities, cellular localization and interacting partners. The specialized roles that base excision repair play in transcriptional activation by active demethylation and targeted oxidation as well as how base excision repair functions in the immune processes of somatic hypermutation and class switch recombination and its possible involvement in retroviral infection are also discussed. Finally the complexities of oxidative damage and its repair and its link to neurodegenerative disorders, as well as the role of base excision repair as a tumor suppressor are examined in the context of damage, repair and aging. By outlining the many base excision repair-related mysteries that have yet to be unraveled, hopefully this perspective will stimulate further interest in the field.

show abstract

Regulation of DNA glycosylases and their role in limiting disease

Abstract: This review will present a current understanding of mechanisms for the initiation of base excision repair (BER) of oxidatively-induced DNA damage and the biological consequences of deficiencies in these enzymes in mouse model systems and human populations.

Cited by 43 publications

References 233 publications

Human Apurinic/Apyrimidinic Endonuclease 1

Human Apurinic/Apyrimidinic Endonuclease 1

Oxidative DNA damage in disease—Insights gained from base excision repair glycosylase‐deficient mouse models

Base excision repair: A critical player in many games

Contact Info

Product

Resources

About