Molecular Mechanisms of H. pylori Induced 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.

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

International Journal of Molecular Sciences ◽

10.3390/ijms19102891 ◽

2018 ◽

Vol 19 (10) ◽

pp. 2891 ◽

Cited By ~ 7

Author(s):

Dawit Kidane

Keyword(s):

Genomic Instability ◽

Oxidative Dna Damage ◽

Molecular Mechanisms ◽

Excision Repair ◽

Current Knowledge ◽

Significant Risk ◽

Significant Risk Factor ◽

Double Strand Breaks ◽

Strand Breaks ◽

H Pylori

Infections contribute to carcinogenesis through inflammation-related mechanisms. H. pylori infection is a significant risk factor for gastric carcinogenesis. However, the molecular mechanism by which H. pylori infection contributes to carcinogenesis 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). Furthermore, we provide mechanistic insight into how processing of oxidative DNA damage via base excision repair (BER) leads to DSBs. We review recent studies on how H. pylori infection triggers NF-κB/inducible NO synthase (iNOS) versus NF-κB/nucleotide excision repair (NER) axis-mediated DSBs to drive genomic instability. This review discusses current research findings that are related to mechanisms of DSBs and repair during H. pylori infection.

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

DNA Repair ◽

10.1016/j.dnarep.2016.03.003 ◽

2016 ◽

Vol 41 ◽

pp. 16-26 ◽

Cited By ~ 5

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 ◽

End Joining ◽

Strand Breaks ◽

Thymine Glycol ◽

MBD4 Facilitates Immunoglobulin Class Switch Recombination

Molecular and Cellular Biology ◽

10.1128/mcb.00316-16 ◽

2016 ◽

Vol 37 (2) ◽

Cited By ~ 7

Author(s):

Fernando Grigera ◽

Robert Wuerffel ◽

Amy L. Kenter

Keyword(s):

Excision Repair ◽

Cytidine Deaminase ◽

Ectopic Expression ◽

Class Switch Recombination ◽

Double Strand Breaks ◽

Strand Breaks ◽

Class Switch ◽

Activation Induced Cytidine Deaminase ◽

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

Journal of Clinical Oncology ◽

10.1200/jco.2007.11.5287 ◽

2007 ◽

Vol 25 (26) ◽

pp. 4043-4050 ◽

Cited By ~ 69

Author(s):

Donna S. Shewach ◽

Theodore S. Lawrence

Keyword(s):

Excision Repair ◽

Growth Factor Receptor ◽

Double Strand Breaks ◽

Egfr Inhibitors ◽

Strand Breaks ◽

Solid Malignancies ◽

Target Dna ◽

Epidermal Growth ◽

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.

OGG1 Inhibitor TH5487 Alters OGG1 Chromatin Dynamics and Prevents Incisions

Biomolecules ◽

10.3390/biom10111483 ◽

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 ◽

Chromatin Dynamics ◽

Strand Breaks ◽

Pathological Conditions ◽

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.

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

The Journal of Cell Biology ◽

10.1083/jcb.201312078 ◽

2014 ◽

Vol 206 (1) ◽

pp. 29-43 ◽

Cited By ~ 65

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 Breaks ◽

Strand Breaks ◽

Single Strand Breaks ◽

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.

Helicobacter pylori Infection Introduces DNA Double-Strand Breaks in Host Cells

Infection and Immunity ◽

10.1128/iai.02368-14 ◽

2014 ◽

Vol 82 (10) ◽

pp. 4182-4189 ◽

Cited By ~ 52

Author(s):

Katsuhiro Hanada ◽

Tomohisa Uchida ◽

Yoshiyuki Tsukamoto ◽

Masahide Watada ◽

Nahomi Yamaguchi ◽

...

Keyword(s):

Gastric Cancer ◽

Helicobacter Pylori ◽

Genomic Instability ◽

Double Strand Breaks ◽

Host Cells ◽

Content Type ◽

Strand Breaks ◽

H Pylori

ABSTRACTGastric cancer is an inflammation-related malignancy related to long-standing acute and chronic inflammation caused by infection with the human bacterial pathogenHelicobacter pylori. Inflammation can result in genomic instability. However, there are considerable data thatH. pyloriitself can also produce genomic instability both directly and through epigenetic pathways. Overall, the mechanisms ofH. pylori-induced host genomic instabilities remain poorly understood. We used microarray screening ofH. pylori-infected human gastric biopsy specimens to identify candidate genes involved inH. pylori-induced host genomic instabilities. We found upregulation ofATMexpressionin vivoin gastric mucosal cells infected withH. pylori. Using gastric cancer cell lines, we confirmed that theH. pylori-related activation of ATM was due to the accumulation of DNA double-strand breaks (DSBs). DSBs were observed following infection with bothcagpathogenicity island (PAI)-positive and -negative strains, but the effect was more robust withcagPAI-positive strains. These results are consistent with the fact that infections with bothcagPAI-positive and -negative strains are associated with gastric carcinogenesis, but the risk is higher in individuals infected withcagPAI-positive strains.

Human papillomavirus E7 oncoprotein targets RNF168 to hijack the host DNA damage response

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1906102116 ◽

2019 ◽

Vol 116 (39) ◽

pp. 19552-19562 ◽

Cited By ~ 7

Author(s):

Justine Sitz ◽

Sophie Anne Blanchet ◽

Steven F. Gameiro ◽

Elise Biquand ◽

Tia M. Morgan ◽

...

Keyword(s):

Cervical Cancer ◽

Dna Damage ◽

Cancer Cells ◽

Genomic Instability ◽

E3 Ligase ◽

Human Papillomaviruses ◽

Double Strand Breaks ◽

Nuclear Bodies ◽

Strand Breaks

High-risk human papillomaviruses (HR-HPVs) promote cervical cancer as well as a subset of anogenital and head and neck cancers. Due to their limited coding capacity, HPVs hijack the host cell’s DNA replication and repair machineries to replicate their own genomes. How this host–pathogen interaction contributes to genomic instability is unknown. Here, we report that HPV-infected cancer cells express high levels of RNF168, an E3 ubiquitin ligase that is critical for proper DNA repair following DNA double-strand breaks, and accumulate high numbers of 53BP1 nuclear bodies, a marker of genomic instability induced by replication stress. We describe a mechanism by which HPV E7 subverts the function of RNF168 at DNA double-strand breaks, providing a rationale for increased homology-directed recombination in E6/E7-expressing cervical cancer cells. By targeting a new regulatory domain of RNF168, E7 binds directly to the E3 ligase without affecting its enzymatic activity. As RNF168 knockdown impairs viral genome amplification in differentiated keratinocytes, we propose that E7 hijacks the E3 ligase to promote the viral replicative cycle. This study reveals a mechanism by which tumor viruses reshape the cellular response to DNA damage by manipulating RNF168-dependent ubiquitin signaling. Importantly, our findings reveal a pathway by which HPV may promote the genomic instability that drives oncogenesis.

ATM-dependent pathways of chromatin remodelling and oxidative DNA damage responses

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2016.0283 ◽

2017 ◽

Vol 372 (1731) ◽

pp. 20160283 ◽

Cited By ~ 25

Author(s):

N. Daniel Berger ◽

Fintan K. T. Stanley ◽

Shaun Moore ◽

Aaron A. Goodarzi

Keyword(s):

Dna Damage ◽

Oxidative Dna Damage ◽

Strand Break ◽

Chromatin Remodelling ◽

Double Strand Breaks ◽

Biochemical Network ◽

Regulatory Function ◽

Strand Breaks ◽

The Impact

Ataxia-telangiectasia mutated (ATM) is a serine/threonine protein kinase with a master regulatory function in the DNA damage response. In this role, ATM commands a complex biochemical network that signals the presence of oxidative DNA damage, including the dangerous DNA double-strand break, and facilitates subsequent repair. Here, we review the current state of knowledge regarding ATM-dependent chromatin remodelling and epigenomic alterations that are required to maintain genomic integrity in the presence of DNA double-strand breaks and/or oxidative stress. We will focus particularly on the roles of ATM in adjusting nucleosome spacing at sites of unresolved DNA double-strand breaks within complex chromatin environments, and the impact of ATM on preserving the health of cells within the mammalian central nervous system. This article is part of the themed issue ‘Chromatin modifiers and remodellers in DNA repair and signalling’.