Is Base Excision Repair a Tumor Suppressor Mechanism?

Sweasy, Joann B.; Lang, Tieming; DiMaio, Daniel

doi:10.4161/cc.5.3.2414

Cited by 73 publications

(52 citation statements)

References 108 publications

(146 reference statements)

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“…Because occurrence of this event is influenced by the repair capacity of the cell, variation in intrinsic Ogg1 within the normal human population (39) could be of great importance. Additionally, mutations in Ogg1 and other BER proteins have been associated with human cancers (40).…”

Section: Discussionmentioning

confidence: 99%

8-Oxoguanine-mediated transcriptional mutagenesis causes Ras activation in mammalian cells

Saxowsky¹,

Meadows²,

Klungland

et al. 2008

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

111

136

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DNA repair ͉ MAP kinase ͉ Csb ͉ transcription-coupled repair ͉ tumorigenesis C ells use numerous mechanisms to neutralize various reactive species before they can damage DNA, as well as overlapping pathways to repair the damage, thus protecting genomic integrity. DNA damage can result in a number of potential outcomes for a mammalian cell (1), including permanent fixation of the damage during replication, leading to a heritable mutation. Replication-centric models of mutagenesis have provided valuable information regarding routes of mutagenesis under conditions of continuous cell growth and replication. These models, however, largely ignore transcription, the other major nucleic acid transaction essential to the cell. In slowly growing or nondividing cells, in which DNA replication is greatly diminished or altogether absent (e.g., terminally differentiated mammalian cells [2]), transcription must continue to provide the cell with the proteins necessary for normal physiologic processes. As such, the interaction of DNA damage with the transcription machinery occurs more frequently than with the replication apparatus.Many types of DNA damage are repaired with greater efficiency if they occur in the template strand of a transcribed gene rather than the nontemplate strand or a nontranscribed region of the genome (3, 4). Bulky lesions that distort the DNA helix will arrest RNA polymerase (RNAP) at the site of damage, promoting transcription-coupled repair (TCR) and allowing the generation of full-length, normal transcripts (5, 6). However, frequently occurring nonbulky lesions, such as 8-oxoguanine

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Section: Discussionmentioning

confidence: 99%

8-Oxoguanine-mediated transcriptional mutagenesis causes Ras activation in mammalian cells

Saxowsky¹,

Meadows²,

Klungland

et al. 2008

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

111

136

View full text Add to dashboard Cite

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“…Subsequently, apurinicapyrimidinic endonuclease-1 (APE1) incises the backbone after which polymerase b fills the single nucleotide gap using the complementary DNA strand as a template (short patch BER) and the nick is sealed by the XRCC1-ligase3 complex. In case of a 2-12 nucleotide gap (long-patch BER) additionally polymerase d/e, proliferating cell nuclear antigen (PCNA), flap endonuclease 1, replication factor C, and DNA Ligase1 (LIGI) are being used [61, 77,78]. PARP1 is thought to function as a SSB damage sensor binding to the SSB after which repair via mostly long-patch BER can take place [79].…”

Section: Base Excision Repairmentioning

confidence: 99%

Genomic instability in breast and ovarian cancers: translation into clinical predictive biomarkers

Vollebergh

Jonkers

Linn

2011

Cell. Mol. Life Sci.

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Breast and ovarian cancer are among the most common malignancies diagnosed in women worldwide. Together, they account for the majority of cancer-related deaths in women. These cancer types share a number of features, including their association with hereditary cancer syndromes caused by heterozygous germline mutations in BRCA1 or BRCA2. BRCA-associated breast and ovarian cancers are hallmarked by genomic instability and high sensitivity to DNA double-strand break (DSB) inducing agents due to loss of error-free DSB repair via homologous recombination (HR). Recently, poly(ADP-ribose) polymerase inhibitors, a new class of drugs that selectively target HR-deficient tumor cells, have been shown to be highly active in BRCA-associated breast and ovarian cancers. This finding has renewed interest in hallmarks of HR deficiency and the use of other DSB-inducing agents, such as platinum salts or bifunctional alkylators, in breast and ovarian cancer patients. In this review we discuss the similarities between breast and ovarian cancer, the hallmarks of genomic instability in BRCA-mutated and BRCA-like breast and ovarian cancers, and the efforts to search for predictive markers of HR deficiency in order to individualize therapy in breast and ovarian cancer.

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“…Oxidative DNA damage is mitigated by a variety of DNA repair pathways (7-9). The importance of repairing DNA damage has been highlighted by the correlation between defects in DNA repair pathways and cancer (7,(10)(11)(12). ¶ This work was supported by a grant from the National Cancer Institute of the National Institutes of Health (CA90689).…”

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confidence: 99%

Superior Removal of Hydantoin Lesions Relative to Other Oxidized Bases by the Human DNA Glycosylase hNEIL1

et al. 2008

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The DNA glycosylase hNEIL1 initiates the base excision repair (BER) of a diverse array of lesions, including ring-opened purines and saturated pyrimidines. Of these, the hydantoin lesions, guanidinohydantoin (Gh) and the two diastereomers of spiroiminodihydantoin (Sp1 and Sp2) have garnered much recent attention due to their unusual structures, high mutagenic potential and detection in cells. In order to provide insight into the role of repair, the excision efficiency by hNEIL1 of these hydantoin lesions relative to other known substrates was determined. Most notably, quantitative examination of the substrate specificity with hNEIL1 revealed that the hydantoin lesions are excised much more efficiently (> 100-fold faster) than the reported standard substrates thymine glycol (Tg) and 5-hydroxycytosine (5-OHC). Importantly, the glycosylase and β,δ-lyase reactions are tightly coupled such that the rate of the lyase activity does not influence the observed substrate specificity. The activity of hNEIL1 is also influenced by the base pair partner of the lesion, with both Gh and Sp removal being more efficient when paired with T, G or C than when paired with A. Notably, the most efficient removal is observed with the Gh or Sp paired in the unlikely physiological context with T; indeed, this may be a consequence of the unstable nature of base pairs with T. However, the facile removal via BER in promutagenic base pairs that are reasonably formed after replication (such as Gh:G) may be a factor that modulates the mutagenic profile of these lesions. In addition, hNEIL1 excises Sp1 faster than Sp2 indicating the enzyme can discriminate between the two diastereomers. This is the first time that a BER glycosylase has been shown to be able to preferentially excise one diastereomer of Sp. This may be a consequence of the architecture of the active site of hNEIL1 and the structural uniqueness of the Sp lesion. These results indicate that the hydantoin lesions are the best substrates identified thus far for hNEIL1, and suggest that repair of these lesions may be a critical function of the hNEIL1 enzyme in vivo.Cells experiencing oxidative stress have an overabundance of reactive oxygen species (ROS) such as superoxide, hydrogen peroxide, and hydroxyl radicals (1,2). ROS are present in cells as byproducts of endogenous metabolic reactions or as a result of external sources such as ionizing radiation. The reactions mediated by ROS can lead to various types of DNA damage including strand breaks, DNA-protein cross-links, abasic sites, and base lesions, which are potentially detrimental to cells (3)(4)(5)(6). Oxidative DNA damage is mitigated by a variety of DNA repair pathways (7-9). The importance of repairing DNA damage has been highlighted by the correlation between defects in DNA repair pathways and cancer (7,(10)(11)(12). ¶ This work was supported by a grant from the National Cancer Institute of the National Institutes of Health (CA90689). Although a variety of guanine oxidation products have been identified (13), most st...

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Is Base Excision Repair a Tumor Suppressor Mechanism?

Cited by 73 publications

References 108 publications

8-Oxoguanine-mediated transcriptional mutagenesis causes Ras activation in mammalian cells

8-Oxoguanine-mediated transcriptional mutagenesis causes Ras activation in mammalian cells

Genomic instability in breast and ovarian cancers: translation into clinical predictive biomarkers

Superior Removal of Hydantoin Lesions Relative to Other Oxidized Bases by the Human DNA Glycosylase hNEIL1

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