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 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.

scholarly journals Nonhomologous end joining of complex DNA double-strand breaks with proximal thymine glycol and interplay with base excision repair

DNA Repair ◽  
2016 ◽  
Vol 41 ◽  
pp. 16-26 ◽  
Author(s):  
Mohammed Almohaini ◽  
Sri Lakshmi Chalasani ◽  
Duaa Bafail ◽  
Konstantin Akopiants ◽  
Tong Zhou ◽  
...  
Keyword(s):  
Base Excision Repair ◽  
Excision Repair ◽  
Double Strand Breaks ◽  
Nonhomologous End Joining ◽  
Dna Double Strand Breaks ◽  
End Joining ◽  
Strand Breaks ◽  
Thymine Glycol ◽  
Base Excision

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 Molecular Mechanisms of H. pylori Induced DNA Double-Strand Breaks

2018 ◽  
Author(s):  
Dawit Kidane
Keyword(s):  
Genomic Instability ◽  
Oxidative Dna Damage ◽  
Molecular Mechanisms ◽  
Excision Repair ◽  
Current Knowledge ◽  
Double Strand Breaks ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Base Excision ◽  
H Pylori

Infections contribute to carcinogenesis through inflammation-related mechanisms. It is well established that H. pylori infection is an etiological factor in gastric carcinogenesis. However, the mechanism through which H. pylori infection contributes to the development of gastric cancer has not been fully elucidated. H. pylori-associated chronic inflammation is linked to genomic instability via reactive oxygen and nitrogen species (RONS). In this article, we summarize the current knowledge of H. pylori-induced double strand breaks (DSBs). Further, we will provide mechanistic insight into how processing of oxidative DNA damage via base excision repair (BER) leads to double strand breaks (DSBs). We review the recent progress how H. pylori infection triggers NF-kB /iNOS versus NF-kB/nucleotide excision repair (NER) axis mediated DSBs to drive genomic instability. Taken together, this review discusses current findings related to DSBs and their implications for the mechanisms of DSB repair.

scholarly journals MBD4 Facilitates Immunoglobulin Class Switch Recombination

2016 ◽  
Vol 37 (2) ◽  
Author(s):  
Fernando Grigera ◽  
Robert Wuerffel ◽  
Amy L. Kenter
Keyword(s):  
Excision Repair ◽  
Cytidine Deaminase ◽  
Ectopic Expression ◽  
Class Switch Recombination ◽  
Double Strand Breaks ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Class Switch ◽  
Activation Induced Cytidine Deaminase ◽  
Base Excision

ABSTRACT Immunoglobulin heavy chain class switch recombination (CSR) requires targeted formation of DNA double-strand breaks (DSBs) in repetitive switch region elements followed by ligation between distal breaks. The introduction of DSBs is initiated by activation-induced cytidine deaminase (AID) and requires base excision repair (BER) and mismatch repair (MMR). The BER enzyme methyl-CpG binding domain protein 4 (MBD4) has been linked to the MMR pathway through its interaction with MutL homologue 1 (MLH1). We find that when Mbd4 exons 6 to 8 are deleted in a switching B cell line, DSB formation is severely reduced and CSR frequency is impaired. Impaired CSR can be rescued by ectopic expression of Mbd4. Mbd4 deficiency yields a deficit in DNA end processing similar to that found in MutS homologue 2 (Msh2)- and Mlh1-deficient B cells. We demonstrate that microhomology-rich S-S junctions are enriched in cells in which Mbd4 is deleted. Our studies suggest that Mbd4 is a component of MMR-directed DNA end processing.

Antimetabolite Radiosensitizers

2007 ◽  
Vol 25 (26) ◽  
pp. 4043-4050 ◽  
Author(s):  
Donna S. Shewach ◽  
Theodore S. Lawrence
Keyword(s):  
Excision Repair ◽  
Growth Factor Receptor ◽  
Double Strand Breaks ◽  
Egfr Inhibitors ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Solid Malignancies ◽  
Target Dna ◽  
Epidermal Growth ◽  
Base Excision

Radiosensitization with antimetabolites has improved clinical outcome for patients with solid malignancies, especially cancers of the GI tract, cervix, and head and neck. Fluorouracil (FU) and hydroxyurea have been widely used clinically during the last four decades, and promising results have been observed more recently with gemcitabine. Although the antimetabolites all target DNA replication, they differ with respect to the mechanisms by which they produce radiosensitization. The antimetabolite radiosensitizers may inhibit thymidylate synthase (TS) or ribonucleotide reductase, and the nucleoside/nucleobase analogs can be incorporated into DNA. Radiosensitization can result from chemotherapy-induced increase in DNA double-strand breaks or inhibition of their repair. Studies of repair pathways involved in radiosensitization with antimetabolites implicate base excision repair with the TS inhibitors, homologous recombination with gemcitabine, and mismatch repair with FU and gemcitabine. Gemcitabine can also stimulate epidermal growth factor receptor (EGFR) phosphorylation; inhibiting this effect with EGFR inhibitors can potentiate cytotoxicity and radiosensitization. Additional work is necessary to determine more precisely the processes by which antimetabolites act as radiation sensitizers and to define the optimal sequencing of these agents with EGFR inhibitors to provide better guidance for clinical protocols combining these drugs with radiotherapy.

scholarly journals OGG1 Inhibitor TH5487 Alters OGG1 Chromatin Dynamics and Prevents Incisions

Biomolecules ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 1483
Author(s):  
Bishoy M. F. Hanna ◽  
Thomas Helleday ◽  
Oliver Mortusewicz
Keyword(s):  
Excision Repair ◽  
Double Strand Breaks ◽  
Dna Glycosylase ◽  
Chromatin Binding ◽  
Dna Double Strand Breaks ◽  
Chromatin Dynamics ◽  
Strand Breaks ◽  
Pathological Conditions ◽  
Base Excision

8-oxoguanine DNA glycosylase (OGG1) is the main DNA glycosylase responsible for the excision of 7,8-dihydro-8-oxoguanine (8-oxoG) from duplex DNA to initiate base excision repair. This glycosylase activity is relevant in many pathological conditions including cancer, inflammation, and neurodegenerative diseases. To have a better understanding of the role of OGG1, we previously reported TH5487, a potent active site inhibitor of OGG1. Here, we further investigate the consequences of inhibiting OGG1 with TH5487. TH5487 treatment induces accumulation of genomic 8-oxoG lesions. Furthermore, it impairs the chromatin binding of OGG1 and results in lower recruitment of OGG1 to regions of DNA damage. Inhibiting OGG1 with TH5487 interferes with OGG1′s incision activity, resulting in fewer DNA double-strand breaks in cells exposed to oxidative stress. This study validates TH5487 as a potent OGG1 inhibitor that prevents the repair of 8-oxoG and alters OGG1–chromatin dynamics and OGG1′s recruitment kinetics.

scholarly journals The Transition of Closely Opposed Lesions to Double-Strand Breaks during Long-Patch Base Excision Repair Is Prevented by the Coordinated Action of DNA Polymerase δ and Rad27/Fen1

2008 ◽  
Vol 29 (5) ◽  
pp. 1212-1221 ◽  
Author(s):  
Wenjian Ma ◽  
Vijayalakshmi Panduri ◽  
Joan F. Sterling ◽  
Bennett Van Houten ◽  
Dmitry A. Gordenin ◽  
...  
Keyword(s):  
Dna Polymerase ◽  
Base Excision Repair ◽  
Excision Repair ◽  
Double Strand Breaks ◽  
Single Strand ◽  
S1 Nuclease ◽  
Single Strand Break ◽  
Strand Breaks ◽  
Dna Polymerase Δ ◽  
Base Excision

ABSTRACT DNA double-strand breaks can result from closely opposed breaks induced directly in complementary strands. Alternatively, double-strand breaks could be generated during repair of clustered damage, where the repair of closely opposed lesions has to be well coordinated. Using single and multiple mutants of Saccharomyces cerevisiae (budding yeast) that impede the interaction of DNA polymerase δ and the 5′-flap endonuclease Rad27/Fen1 with the PCNA sliding clamp, we show that the lack of coordination between these components during long-patch base excision repair of alkylation damage can result in many double-strand breaks within the chromosomes of nondividing haploid cells. This contrasts with the efficient repair of nonclustered methyl methanesulfonate-induced lesions, as measured by quantitative PCR and S1 nuclease cleavage of single-strand break sites. We conclude that closely opposed single-strand lesions are a unique threat to the genome and that repair of closely opposed strand damage requires greater spatial and temporal coordination between the participating proteins than does widely spaced damage in order to prevent the development of double-strand breaks.

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.

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