Helicobacter pylori CagA elicits BRCAness to induce genome instability that may underlie bacterial gastric carcinogenesis

Imai, Satoshi; Ooki, Takuya; Murata‐Kamiya, Naoko; Komura, Daisuke; Tahmina, Kamrunnesa; Wu, Weida; Takahashi-Kanemitsu, Atsushi; Knight, Christopher T. G.; Kunita, Akiko; Suzuki, Nobumi; Valle, Adriana A. Del; Tsuboi, Masamichi; Hata, Mitsumasa; Hayakawa, Yoku; Ohnishi, Naomi; Ueda, Koji; Fukayama, Masashi; Ushiku, Tetsuo; Ishikawa, Shumpei; Hatakeyama, Masanori

doi:10.1016/j.chom.2021.04.006

Cited by 91 publications

(97 citation statements)

References 86 publications

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“…Moreover, CagA-dependent DSB accumulation was particularly more pronounced in the S phase of cell cycle, as revealed through the co-staining of γH2AX with the S phase marker, 5-ethynyl-2 -deoxyuridine (EdU) (Figure 1G-H). However, consistent with previous reports [13,15], cell cycle analyses suggested that after 48 h of CagA expression, there is a significant proportion of cells accumulated in G1 (Figure 1I). Our results demonstrate that CagA expression was sufficient to trigger genomic DNA DSBs within the host.…”

Section: Caga Induces Host Double Strand Breaks and Downregulates Fa Repair Factorssupporting

confidence: 93%

“…A doxycycline-inducible CagA model was used to examine the relationship between CagA expression and DSB induction. As described earlier [8,13,14], upon doxycycline with-drawal, CagA-expressing MKN28 cells exhibited characteristic hummingbird morphology and upregulation of IL-8 and MMP-9 (Figure 1A-C and Figure S1A), demonstrating that CagA was functional and recapitulated the known effects of this bacterial protein on gastric epithelial cells. Employing this system, we asked if CagA expression triggers spontaneous DSBs.…”

Section: Caga Induces Host Double Strand Breaks and Downregulates Fa Repair Factorssupporting

confidence: 74%

“…More recently, CagA-dependent inhibition of Par1b, a member of the PAR1 serine/threonine kinase family of proteins was shown to induce CagA-dependent DSBs [5]. Consistently, the re-introduction of ectopic Par1b rescued the DSBs induced by CagA-positive H. pylori by preventing BRCAness [13].…”

Section: Introductionmentioning

confidence: 80%

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The H. pylori CagA Oncoprotein Induces DNA Double Strand Breaks through Fanconi Anemia Pathway Downregulation and Replication Fork Collapse

Kolinjivadi

Sankar

Krishnan

et al. 2022

IJMS

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The proteins from the Fanconi Anemia (FA) pathway of DNA repair maintain DNA replication fork integrity by preventing the unscheduled degradation of nascent DNA at regions of stalled replication forks. Here, we ask if the bacterial pathogen H. pylori exploits the fork stabilisation machinery to generate double stand breaks (DSBs) and genomic instability. Specifically, we study if the H. pylori virulence factor CagA generates host genomic DSBs through replication fork destabilisation and collapse. An inducible gastric cancer model was used to examine global CagA-dependent transcriptomic and proteomic alterations, using RNA sequencing and SILAC-based mass spectrometry, respectively. The transcriptional alterations were confirmed in gastric cancer cell lines infected with H. pylori. Functional analysis was performed using chromatin fractionation, pulsed-field gel electrophoresis (PFGE), and single molecule DNA replication/repair fiber assays. We found a core set of 31 DNA repair factors including the FA genes FANCI, FANCD2, BRCA1, and BRCA2 that were downregulated following CagA expression. H. pylori infection of gastric cancer cell lines showed downregulation of the aforementioned FA genes in a CagA-dependent manner. Consistent with FA pathway downregulation, chromatin purification studies revealed impaired levels of Rad51 but higher recruitment of the nuclease MRE11 on the chromatin of CagA-expressing cells, suggesting impaired fork protection. In line with the above data, fibre assays revealed higher fork degradation, lower fork speed, daughter strands gap accumulation, and impaired re-start of replication forks in the presence of CagA, indicating compromised genome stability. By downregulating the expression of key DNA repair genes such as FANCI, FANCD2, BRCA1, and BRCA2, H. pylori CagA compromises host replication fork stability and induces DNA DSBs through fork collapse. These data unveil an intriguing example of a bacterial virulence factor that induces genomic instability by interfering with the host replication fork stabilisation machinery.

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Section: Caga Induces Host Double Strand Breaks and Downregulates Fa Repair Factorssupporting

confidence: 93%

Section: Caga Induces Host Double Strand Breaks and Downregulates Fa Repair Factorssupporting

confidence: 74%

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The H. pylori CagA Oncoprotein Induces DNA Double Strand Breaks through Fanconi Anemia Pathway Downregulation and Replication Fork Collapse

Kolinjivadi

Sankar

Krishnan

et al. 2022

IJMS

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“…On the other hand, nonphosphorylated CagA interacts with several other cellular components, such as Grb2, which leads to loss of cell polarity, mitogenic responses, and proinflammatory signaling [58,59]. In its molecular involvement during carcinogenesis, CagA protein was identified to inhibit PAR1b-mediated BRCA1 phosphorylation, enhance DNA double breaks, and stimulate Hippo signaling, all of which drive genome instability during development of cancer-predisposing cells [60]. Activation of YAP signaling by CagA was further observed to promote epithelial mesenchymal transition in the gastric epithelial cells, thereby accelerating carcinogenesis and cancer dissemination [61].…”

Section: Caga Perturbs Normal Cell Activitiesmentioning

confidence: 99%

An Overview of Helicobacter pylori Survival Tactics in the Hostile Human Stomach Environment

et al. 2021

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Helicobacter pylori is well established as a causative agent for gastritis, peptic ulcer, and gastric cancer. Armed with various inimitable virulence factors, this Gram-negative bacterium is one of few microorganisms that is capable of circumventing the harsh environment of the stomach. The unique spiral structure, flagella, and outer membrane proteins accelerate H. pylori movement within the viscous gastric mucosal layers while facilitating its attachment to the epithelial cells. Furthermore, secretion of urease from H. pylori eases the acidic pH within the stomach, thus creating a niche for bacteria survival and replication. Upon gaining a foothold in the gastric epithelial lining, bacterial protein CagA is injected into host cells through a type IV secretion system (T4SS), which together with VacA, damage the gastric epithelial cells. H. pylori does not only establishes colonization in the stomach, but also manipulates the host immune system to permit long-term persistence. Prolonged H. pylori infection causes chronic inflammation that precedes gastric cancer. The current review provides a brief outlook on H. pylori survival tactics, bacterial-host interaction and their importance in therapeutic intervention as well as vaccine development.

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“…The most widely recognized microbe association with cancer is Helicobacter pylori infection and its interactions with gastric cancer. 19 In addition, research has also found that oral pathogens have a place in the occurrence and development of CRC, 20 including Fusobacterium nucleatum ( F. nucleatum ) 21 and Porphyromonas gingivalis ( P. gingivalis ), 22 which are the most widely implicated to date. Most of these pathogens are common pathogenic bacteria observed in periodontitis, causing an inflammatory environment in periodontal tissue and regulating immune responses.…”

Section: Introductionmentioning

confidence: 99%

Oral-Intestinal Microbiota in Colorectal Cancer: Inflammation and Immunosuppression

Mo¹,

Ru²,

Huang³

et al. 2022

JIR

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It is widely recognized that microbial disorders are involved in the pathogenesis of many malignant tumors. The oral and intestinal tract are two of the overriding microbial habitats in the human body. Although they are anatomically and physiologically continuous, belonging to the openings at both ends of the digestive tract, the oral and intestinal microbiome do not cross talk with each other due to a variety of reasons, including intestinal microbial colonization resistance and chemical barriers in the upper digestive tract. However, this balance can be upset in certain circumstances, such as disruption of colonization resistance of gut microbes, intestinal inflammation, and disruption of the digestive tract chemical barrier. Evidence is now accruing to suggest that the oral microbiome can colonize the gut, leading to dysregulation of the gut microbes. Furthermore, the oral-gut microbes create an intestinal inflammatory and immunosuppressive microenvironment conducive to tumorigenesis and progression of colorectal cancer (CRC). Here, we review the oral to intestinal microbial transmission and the inflammatory and immunosuppressive microenvironment, induced by oral-gut axis microbes in the gut. A superior comprehension of the contribution of the oral-intestinal microbes to CRC provides new insights into the prevention and treatment of CRC in the future.

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Helicobacter pylori CagA elicits BRCAness to induce genome instability that may underlie bacterial gastric carcinogenesis

Cited by 91 publications

References 86 publications

The H. pylori CagA Oncoprotein Induces DNA Double Strand Breaks through Fanconi Anemia Pathway Downregulation and Replication Fork Collapse

The H. pylori CagA Oncoprotein Induces DNA Double Strand Breaks through Fanconi Anemia Pathway Downregulation and Replication Fork Collapse

An Overview of Helicobacter pylori Survival Tactics in the Hostile Human Stomach Environment

Oral-Intestinal Microbiota in Colorectal Cancer: Inflammation and Immunosuppression

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