scholarly journals Base excision repair and its implications to cancer therapy

2020 ◽  
Vol 64 (5) ◽  
pp. 831-843 ◽  
Author(s):  
Gabrielle J. Grundy ◽  
Jason L. Parsons
Keyword(s):  
Oxidative Stress ◽  
Cancer Cells ◽  
Base Excision Repair ◽  
Excision Repair ◽  
Repair Process ◽  
Loss Of Function ◽  
Strand Breaks ◽  
Single Strand Breaks ◽  
Base Excision ◽  
Integrity Of Dna

Abstract Base excision repair (BER) has evolved to preserve the integrity of DNA following cellular oxidative stress and in response to exogenous insults. The pathway is a coordinated, sequential process involving 30 proteins or more in which single strand breaks are generated as intermediates during the repair process. While deficiencies in BER activity can lead to high mutation rates and tumorigenesis, cancer cells often rely on increased BER activity to tolerate oxidative stress. Targeting BER has been an attractive strategy to overwhelm cancer cells with DNA damage, improve the efficacy of radiotherapy and/or chemotherapy, or form part of a lethal combination with a cancer specific mutation/loss of function. We provide an update on the progress of inhibitors to enzymes involved in BER, and some of the challenges faced with targeting the BER pathway.

scholarly journals JWA regulates XRCC1 and functions as a novel base excision repair protein in oxidative-stress-induced DNA single-strand breaks

2009 ◽  
Vol 37 (6) ◽  
pp. 1936-1950 ◽  
Author(s):  
Shouyu Wang ◽  
Zhenghua Gong ◽  
Rui Chen ◽  
Yunru Liu ◽  
Aiping Li ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Base Excision Repair ◽  
Excision Repair ◽  
Single Strand ◽  
Strand Breaks ◽  
Single Strand Breaks ◽  
Repair Protein ◽  
Base Excision

scholarly journals PARP1 and PARP2 stabilise replication forks at base excision repair intermediates through Fbh1-dependent Rad51 regulation

2018 ◽  
Author(s):  
George E. Ronson ◽  
Ann Liza Piberger ◽  
Martin R. Higgs ◽  
Anna L. Olsen ◽  
Grant S. Stewart ◽  
...  
Keyword(s):  
Base Excision Repair ◽  
Damage Tolerance ◽  
Excision Repair ◽  
Replication Forks ◽  
Strand Breaks ◽  
Single Strand Breaks ◽  
Dna Base ◽  
Repair Mechanisms ◽  
Base Excision

AbstractPARP1 regulates the repair of DNA single strand breaks (SSBs) generated directly, or during base excision repair (BER). However, the role of PARP2 in these and other repair mechanisms is unknown. Here, we report a requirement for PARP2 in stabilising replication forks that encounter BER intermediates through Fbh1-dependent regulation of Rad51. Whilst PARP2 is dispensable for tolerance of cells to SSBs or homologous recombination dysfunction, it is redundant with PARP1 in BER. Therefore, combined disruption of PARP1 and PARP2 leads to defective BER, resulting in elevated levels of replication associated DNA damage due to an inability to stabilise Rad51 at damaged replication forks and prevent uncontrolled DNA resection. Together, our results demonstrate how PARP1 and PARP2 regulate two independent, but intrinsically linked aspects of DNA base damage tolerance by promoting BER directly, and through stabilising replication forks that encounter BER intermediates.

Role of metformin on base excision repair pathway in p53 wild-type H2009 and HepG2 cancer cells

2017 ◽  
Vol 37 (9) ◽  
pp. 909-919 ◽  
Author(s):  
Irem Dogan Turacli ◽  
Tuba Candar ◽  
Berrin Emine Yuksel ◽  
Selda Demirtas
Keyword(s):  
Oxidative Stress ◽  
Cancer Cells ◽  
Base Excision Repair ◽  
Molecular Mechanisms ◽  
Excision Repair ◽  
Single Agent ◽  
Tumor Formation ◽  
Dna Base Excision Repair ◽  
Cellular Signal ◽  
Base Excision

The antidiabetic agent metformin was shown to further possess chemopreventive and chemotherapeutic effects against cancer. Despite the advances, the underlying molecular mechanisms involved in decreasing tumor formation are still unclear. The understanding of the participation of oxidative stress in the action mechanism of metformin and its related effects on p53 and on DNA base excision repair (BER) system can help us to get closer to solve metformin puzzle in cancer. We investigated the effects of metformin in HepG2 and H2009 cells, verifying cytotoxicity, oxidative stress, antioxidant status, and DNA BER system. Our results showed metformin induced oxidative stress and reduced antioxidant capacity. Also, metformin treatment with hydrogen peroxide (H2O2) enhanced these effects. Although DNA BER enzyme activities were not changed accordantly together by metformin as a single agent or in combination with H2O2, activated p53 was decreased with increased oxidative stress in H2009 cells. Our study on the relationship between metformin/reactive oxygen species and DNA BER system in cancer cells would be helpful to understand the anticancer effects of metformin through cellular signal transduction pathways. These findings can be a model of the changes on oxidative stress that reflects p53’s regulatory role on DNA repair systems in cancer for the future studies.

scholarly journals Accumulation of true single strand breaks and AP sites in base excision repair deficient cells

2010 ◽  
Vol 694 (1-2) ◽  
pp. 65-71 ◽  
Author(s):  
April M. Luke ◽  
Paul D. Chastain ◽  
Brian F. Pachkowski ◽  
Valeriy Afonin ◽  
Shunichi Takeda ◽  
...  
Keyword(s):  
Base Excision Repair ◽  
Excision Repair ◽  
Single Strand ◽  
Strand Breaks ◽  
Single Strand Breaks ◽  
Ap Sites ◽  
Base Excision

scholarly journals DNA breaks and chromosomal aberrations arise when replication meets base excision repair

2014 ◽  
Vol 206 (1) ◽  
pp. 29-43 ◽  
Author(s):  
Michael Ensminger ◽  
Lucie Iloff ◽  
Christian Ebel ◽  
Teodora Nikolova ◽  
Bernd Kaina ◽  
...  
Keyword(s):  
Base Excision Repair ◽  
Chromosomal Aberrations ◽  
Excision Repair ◽  
Double Strand Breaks ◽  
Replication Forks ◽  
Dna Double Strand Breaks ◽  
Dna Breaks ◽  
Strand Breaks ◽  
Single Strand Breaks ◽  
Base Excision

Exposures that methylate DNA potently induce DNA double-strand breaks (DSBs) and chromosomal aberrations, which are thought to arise when damaged bases block DNA replication. Here, we demonstrate that DNA methylation damage causes DSB formation when replication interferes with base excision repair (BER), the predominant pathway for repairing methylated bases. We show that cells defective in the N-methylpurine DNA glycosylase, which fail to remove N-methylpurines from DNA and do not initiate BER, display strongly reduced levels of methylation-induced DSBs and chromosomal aberrations compared with wild-type cells. Also, cells unable to generate single-strand breaks (SSBs) at apurinic/apyrimidinic sites do not form DSBs immediately after methylation damage. In contrast, cells deficient in x-ray cross-complementing protein 1, DNA polymerase β, or poly (ADP-ribose) polymerase 1 activity, all of which fail to seal SSBs induced at apurinic/apyrimidinic sites, exhibit strongly elevated levels of methylation-induced DSBs and chromosomal aberrations. We propose that DSBs and chromosomal aberrations after treatment with N-alkylators arise when replication forks collide with SSBs generated during BER.

scholarly journals Bacterial DNA repair genes and their eukaryotic homologues: 1. Mutations in genes involved in base excision repair (BER) and DNA-end processors and their implication in mutagenesis and human disease.

2007 ◽  
Vol 54 (3) ◽  
pp. 413-434 ◽  
Author(s):  
Joanna Krwawicz ◽  
Katarzyna D Arczewska ◽  
Elzbieta Speina ◽  
Agnieszka Maciejewska ◽  
Elzbieta Grzesiuk
Keyword(s):  
Base Excision Repair ◽  
Excision Repair ◽  
Dna Bases ◽  
Cancer Therapies ◽  
Strand Breaks ◽  
Single Strand Breaks ◽  
Modified Dna ◽  
Environmental Agents ◽  
Base Excision ◽  
Bacterial Mutagenesis

Base excision repair (BER) pathway executed by a complex network of proteins is the major system responsible for the removal of damaged DNA bases and repair of DNA single strand breaks (SSBs) generated by environmental agents, such as certain cancer therapies, or arising spontaneously during cellular metabolism. Both modified DNA bases and SSBs with ends other than 3'-OH and 5'-P are repaired either by replacement of a single or of more nucleotides in the processes called short-patch BER (SP-BER) or long-patch BER (LP-BER), respectively. In contrast to Escherichia coli cells, in human ones, the two BER sub-pathways are operated by different sets of proteins. In this review the selection between SP- and LP-BER and mutations in BER and end-processors genes and their contribution to bacterial mutagenesis and human diseases are considered.

scholarly journals Effect of DNA Glycosylases OGG1 and Neil1 on Oxidized G-Rich Motif in the KRAS Promoter

2021 ◽  
Vol 22 (3) ◽  
pp. 1137
Author(s):  
Annalisa Ferino ◽  
Luigi E. Xodo
Keyword(s):  
Oxidative Stress ◽  
Base Excision Repair ◽  
Excision Repair ◽  
Start Site ◽  
Dna Glycosylases ◽  
Repair Pathway ◽  
Transcription Start ◽  
G Quadruplex ◽  
Base Excision ◽  
Regulatory Functions

The promoter of the Kirsten ras (KRAS) proto-oncogene contains, upstream of the transcription start site, a quadruplex-forming motif called 32R with regulatory functions. As guanine under oxidative stress can be oxidized to 8-oxoguanine (8OG), we investigated the capacity of glycosylases 8-oxoguanine glycosylase (OGG1) and endonuclease VIII-like 1 (Neil1) to excise 8OG from 32R, either in duplex or G-quadruplex (G4) conformation. We found that OGG1 efficiently excised 8OG from oxidized 32R in duplex but not in G4 conformation. By contrast, glycosylase Neil1 showed more activity on the G4 than the duplex conformation. We also found that the excising activity of Neil1 on folded 32R depended on G4 topology. Our data suggest that Neil1, besides being involved in base excision repair pathway (BER), could play a role on KRAS transcription.

scholarly journals Stimulation of NEIL2-mediated Oxidized Base Excision Repair via YB-1 Interaction during Oxidative Stress

2007 ◽  
Vol 282 (39) ◽  
pp. 28474-28484 ◽  
Author(s):  
Soumita Das ◽  
Ranajoy Chattopadhyay ◽  
Kishor K. Bhakat ◽  
Istvan Boldogh ◽  
Kimitoshi Kohno ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Base Excision Repair ◽  
Excision Repair ◽  
Base Excision ◽  
Stimulation Of

Studies on the base excision repair (BER) complex in Pyrococcus furiosus

2009 ◽  
Vol 37 (1) ◽  
pp. 79-82 ◽  
Author(s):  
Shinichi Kiyonari ◽  
Saki Tahara ◽  
Maiko Uchimura ◽  
Tsuyoshi Shirai ◽  
Sonoko Ishino ◽  
...  
Keyword(s):  
Base Excision Repair ◽  
Pyrococcus Furiosus ◽  
Excision Repair ◽  
Repair Process ◽  
Nuclear Antigen ◽  
Physical Interaction ◽  
Ap Endonuclease ◽  
Reading Frame ◽  
Base Excision

We have been studying the functions of PCNA (proliferating-cell nuclear antigen) for the assembly and reassembly of the replisome during replication fork progression. We have identified the functional interactions between PCNA and several proteins involved in DNA replication and repair from Pyrococcus furiosus. We recently reported that the activity of UDG (uracil–DNA glycosylase) in P. furiosus (PfuUDG) is stimulated by PCNA (PfuPCNA) in vitro, and identified an atypical PCNA-binding site, AKTLF, in the PfuUDG protein. To understand further the function of the complex in the BER (base excision repair) process, we investigated the AP (apurinic/apyrimidinic) endonuclease, which can process the BER pathway after uracil removal by UDG. Interestingly, one candidate ORF (open reading frame) for the AP endonuclease was found in the operon containing the gene encoding UDG in the P. furiosus genome. However, this ORF did not exhibit any activity. Instead, we identified the AP endonuclease activity from the other candidate gene products, and designated the protein as PfuAP. We discovered a physical interaction between PfuAP and PfuPCNA, suggesting the formation of a BER complex in one of the repair systems in P. furiosus.

Sign in / Sign up

Export Citation Format

Share Document