Overview of Base Excision Repair Biochemistry

Kim, Yun-Jeong; Wilson, David M.

doi:10.2174/1874467211205010003

Cited by 258 publications

(171 citation statements)

References 113 publications

(122 reference statements)

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“…Singlestrand break repair, which is a specialized process that is used for dealing with abnormal 3¢-or 5¢-termini that block DNA polymerase or ligase activity, also engages many of the core BER proteins. For a more detailed discussion of BER, its protein components, and its relationship to disease and other processes, the readers are directed to (39,109) and the accompanying review by Izumi and colleagues.…”

Section: Figmentioning

confidence: 99%

Human Apurinic/Apyrimidinic Endonuclease 1

2014

Antioxidants & Redox Signaling

217

221

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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,

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Section: Figmentioning

confidence: 99%

Human Apurinic/Apyrimidinic Endonuclease 1

2014

Antioxidants & Redox Signaling

217

221

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“…The newly generated abasic site is a substrate for an AP endonuclease that will generate a strand break leaving a 3ЈOH group and a 5Ј-deoxyribose phosphate. The latter is then removed, and the gap is filled by a DNA polymerase and sealed by a DNA ligase (4).…”

mentioning

confidence: 99%

Crystal Structure of the Vaccinia Virus Uracil-DNA Glycosylase in Complex with DNA

Burmeister¹,

Tarbouriech²,

Fender³

et al. 2015

Journal of Biological Chemistry

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Background: D4 is a uracil-DNA glycosylase (UNG) and an essential component of the vaccinia virus DNA polymerase holoenzyme. Results: The crystal structure of D4 in complex with DNA is presented. Conclusion: The D4⅐DNA contacts exhibit major differences compared with the human UNG⅐DNA complex. Significance: This work allows a better understanding of the structural determinants required for UNG function.

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“…We therefore focused on N 7 ‐MeG and N 3 ‐MeA adducts which constitute over 90% of TMZ‐induced base alterations. These are recognized by the BER glycosylase MPG which performs the initial cleavage of the glycosylic bond between the damaged base and deoxyribose to generate an AP site (Bobola et al ., 2012; Kim and Wilson, 2012). Treatment of human GBM cells with RXFP1 agonist CTRP8 increased MPG protein levels and MPG activity as determined by MPG molecular beacon assay, while the cellular levels of other BER proteins, including APE1, DNA polymerase β (polβ), and XRCC1, remained unaffected by CTRP8‐mediated RXFP1 activation.…”

Section: Discussionmentioning

confidence: 99%

“…The methylation at the N 7 position of guanine (N 7 ‐MeG; 80–85%) and the N 3 position of adenine (N 3 ‐MeA; 8–18%) constitute the majority of TMZ‐induced DNA methylations repaired by the base excision repair (BER) pathway. BER is the predominant DNA repair system in mammalian cells and repairs small cytotoxic DNA base lesions resulting from oxidized, alkylated, or deaminated nucleotides (Kim and Wilson, 2012; Krokan and Bjoras, 2013). The remaining 5–10% of TMZ‐induced DNA‐methylated lesions occur as O 6 ‐MeG which is the substrate for the enzyme O 6 ‐methylguanine‐DNA methyltransferase (MGMT) (Sarkaria et al ., 2008).…”

Section: Introductionmentioning

confidence: 99%

“…DNA polymerase β adds the complementary base and the X‐ray repair cross‐complementing group 1 (XRCC1)/DNA ligase III complex performs the phosphodiester bond formation to complete BER (Krokan and Bjoras, 2013). Inhibition of BER in MPG overexpressing human glioma sensitizes these cells to TMZ in vitro and in vivo , but this cytotoxic effect is diminished at higher cellular levels of the rate‐limiting BER enzyme DNA polymerase β (Kim and Wilson, 2012; Tang et al ., 2011). …”

Section: Introductionmentioning

confidence: 99%

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C1q/TNF‐related peptide 8 (CTRP8) promotes temozolomide resistance in human glioblastoma

et al. 2018

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The C1q/TNF‐related peptide 8 (CTRP8) has recently emerged as a novel ligand of the G protein‐coupled receptor RXFP1 in the fatal brain tumor glioblastoma (GBM). We previously demonstrated that the CTRP8‐RXFP1 ligand–receptor system promotes motility and matrix invasion of patient GBM and U87 MG cells by specific phosphorylation of PI3 kinase and protein kinase C. Here, we demonstrate a novel role for CTRP8 in protecting human GBM cells against the DNA alkylating damage of temozolomide (TMZ), the standard chemotherapy drug used to treat GBM. This DNA protective role of CTRP8 required a functional RXFP1‐STAT3 signaling cascade in GBM cells. We identified N‐methylpurine DNA glycosylase (MPG), a monofunctional glycosylase that initiates base excision repair pathway by generating an apurinic/apyrimidinic (AP) site, as a new CTRP8‐RXFP1‐STAT3 target in GBM. Upon TMZ exposure, treatment with CTRP8 reduced the formation of AP sites and double‐strand DNA breaks in GBM cells. This CTRP8 effect was independent of cellular MGMT levels and was associated with decreased caspase 3/7 activity and increased survival of human GBM. CTRP8‐induced RXFP1 activation caused an increase in cellular protein levels of the anti‐apoptotic Bcl members and STAT3 targets Bcl‐2 and Bcl‐XL in human GBM. Collectively, our results demonstrate a novel multipronged and clinically relevant mechanism by which the CTRP8‐RXFP1 ligand–receptor system exerts a DNA protective function against TMZ chemotherapeutic stress in GBM. This CTRP8‐RXFP1‐STAT3 axis is a novel determinant of TMZ responsiveness/chemoresistance and an emerging new drug target for improved treatment of human GBM.

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Overview of Base Excision Repair Biochemistry

Cited by 258 publications

References 113 publications

Human Apurinic/Apyrimidinic Endonuclease 1

Human Apurinic/Apyrimidinic Endonuclease 1

Crystal Structure of the Vaccinia Virus Uracil-DNA Glycosylase in Complex with DNA

C1q/TNF‐related peptide 8 (CTRP8) promotes temozolomide resistance in human glioblastoma

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