Checkpoint kinase 2 is required for efficient immunoglobulin diversification

Davari, Kathrin; Frankenberger, Samantha; Schmidt, Angelika; Tomi, Nils-Sebastian; Jungnickel, Berit

doi:10.4161/15384101.2014.964112

Cited by 10 publications

(9 citation statements)

References 65 publications

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“…The reaction pathway is activated following DNA damage, leading to stagnation of the cell cycle, providing time for damage repair, and inducing gene transcription to facilitate repair at the same time (38). If DNA damage is unable to repair, the damaged cell can initiate apoptosis, and CHEK2 kinase may be involved in the DNA damage caused by cell apoptosis (39). Defects of the DNA damage response pathway leads to genomic instability and cancer susceptibility.…”

Section: Discussionmentioning

confidence: 99%

Associations between mutations of the cell cycle checkpoint kinase 2 gene and gastric carcinogenesis

Hong

Shi

Zhang

et al. 2017

Molecular Medicine Reports

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Gastric cancer is the most common malignant tumor of the digestive system. The etiology of gastric cancer is complex, and susceptibility at the genetic level remains to be fully elucidated in genetic investigations. In the present study, mutations of the cell cycle checkpoint kinase 2 (CHEK2) gene and its association with gastric cancer were examined. Reverse transcription‑quantitative polymerase chain reaction technology was used to detect the expression of CHEK2 and it was found that the expression of CHEK2 was low in gastric cancer. Using sequencing analysis, it was found that the low expression level of CHEK2 was associated with expression of its mutation. The present study also established a CHEK2‑overexpressing mutant and confirmed that CHEK2 promoted gastric cancer cell proliferation. Overexpression of the CHEK2 mutation was confirmed to promote cancer cell migration and invasion. Furthermore, western blot analysis results revealed that overexpression of the CHEK2 mutation downregulated E‑cadherin and upregulated vimentin expression, indicating the mechanism underlying the altered biological behavior. These results suggested that there was a correlation between mutation of the CHEK2 gene and gastric cancer, and provided an experimental basis for antitumor drug investigation and development according to its mutation target.

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Section: Discussionmentioning

confidence: 99%

Associations between mutations of the cell cycle checkpoint kinase 2 gene and gastric carcinogenesis

Hong

Shi

Zhang

et al. 2017

Molecular Medicine Reports

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“…The rare variant we identified, T410fsX14, is a truncating mutation in the distal end of the kinase domain and is probably a loss-of-function mutation. Chk2 inactivation in mouse B cells leads to decreased Ig hypermutation and Ig class switching 42 , conditions that can, along with a DNA repair defect, lead to immune dysregulation 43–45 . Defective DNA repair could also underlie the effects of the S44W PPM1D variant on immune function.…”

Section: Resultsmentioning

confidence: 99%

Identification of ultra-rare genetic variants in Pediatric Acute Onset Neuropsychiatric Syndrome (PANS) by exome and whole genome sequencing

Trifiletti¹,

Manusama

et al. 2021

Preprint

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Pediatric acute onset neuropsychiatric syndrome (PANS) is viewed as an autoimmune/autoinflammatory condition characterized by the abrupt onset of severe neurological and psychiatric symptoms, in particular obsessive-compulsive disorder (OCD), tics, anxiety, mood swings, irritability, and restricted eating, often triggered by infections. However, direct evidence of autoimmunity, infections, or a proinflammatory state is often lacking, and there is no unifying pathogenic pathway. This could be due to underlying genetic heterogeneity, which could lead to the development of PANS through different cellular and molecular pathways. Unfortunately, little is known about the genetic basis of PANS. Consequently, we carried out whole exome sequencing (WES) on a U.S. cohort of 386 cases who met diagnostic criteria for PANS, including 133 family triads, and whole genome sequencing (WGS) on ten cases from the European Union, who were selected for WGS because of severe PANS symptoms. We focused on identifying potentially deleterious genetic variants that were either de novo or ultra-rare with a minor allele frequency (MAF) < 0.001. Candidate mutations were found in 11 genes: PPM1D, SGCE, PLCG2, NLRC4, CACNA1B, SHANK3, CHK2, GRIN2A, RAG1, GABRG2, and SYNGAP1 in a total of 20 cases, which included two sets of siblings, and two or more unrelated subjects with ultra-rare variants in SGCE, NLRC4, RAG1, and SHANK3. The PANS candidate genes we identified separate into two broad functional categories. One group regulates peripheral innate and adaptive immune responses (e.g., PPM1D, CHK2, NLRC4, RAG1, PLCG2), some of which also influence microglia function. Another is expressed primarily at neuronal synapses or directly modulates synaptic function (SHANK3, SYNGAP1, GRIN2A, GABRG2, CACNA1B, SGCE). These neuronal PANS candidate genes are often mutated in autism spectrum disorder, developmental disorders, and myoclonus-dystonia. In fact, eight out of 20 cases in this study developed PANS superimposed on a preexisting neurodevelopmental disorder. There is, however, clinical overlap between these two groups and some crossover expression (e.g., some neuronal genes are expressed in immune cells and vice versa) that diminishes the neuronal/immune dichotomy. Genes in both categories are also highly expressed in the enteric nervous system, and in the choroid plexus and brain vasculature, suggesting they might contribute to a breach in the blood-CSF barrier and blood-brain barrier (BBB) that would permit the entry of autoantibodies, inflammatory cytokines, chemokines, prostaglandins, and autoantibodies into the brain. Thus, PANS is a genetically heterogeneous condition that can occur as a stand-alone neuropsychiatric condition or co-morbid with neurodevelopmental disorders, with candidate genes functioning at several levels of the neuroinflammatory axis.

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“…These results are at odds with our previous findings in vitro on the chicken lymphoma B-cell line DT40 and the human Burkitt lymphoma cell line RAMOS. 25,26 The reason may be that in chicken and human lymphoma cell lines, on the one hand, the lack of p53 function desensitizes the cells to DNA damage-induced apoptosis 43,44 and, on the other hand, the overexpression of the proto-oncogene myc fuels proliferation, ensuring the transmission of mutations. 45,46 In our previous studies on these cell lines, we found that the downregulation or the chemical inhibition of Chk1 leads to an increase of the mutation frequency in the Ig locus, while a stronger Chk1 activation in the absence of Chk2 has opposite effects.…”

Section: Discussionmentioning

confidence: 99%

“…23,24 In our previous studies we have inactivated Chk1 and Chk2 in hypermutating cell lines in order to investigate the effects of checkpoint signaling alteration on the repair pathway choice during SHM. 25,26 Intriguingly, this resulted in opposing phenotypes: while SHM was found to be increased upon (partial) Chk1 inactivation, it was decreased upon Chk2 inactivation, likely because of increased Chk1 activation in Chk2-deficient cells. A defect in the activation of the error-free mechanism of HR upon Chk1 downregulation was found to be responsible for the observed effects, in line with the established role of Chk1 in promoting HR.…”

Section: Introductionmentioning

confidence: 99%

Impact of Chk1 dosage on somatic hypermutation in vivo

Bello

Jungnickel

2021

Immunol Cell Biol

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Checkpoint signaling in the context of a functional DNA damage response is crucial for the prevention of oncogenic transformation of cells. Our immune system, though, takes the risk of attenuated checkpoint responses during immunoglobulin diversification. B cells undergo continuous DNA damage and error-prone repair of their immunoglobulin genes during the process of somatic hypermutation. An accompanying attenuation of the DNA damage response via the ATR-Chk1 axis in B cells is believed to allow for a better DNA damage tolerance and for evasion of apoptosis, so as to ensure mutations to be passed on. We sought to determine whether the downregulation of Chk1 could also directly influence the process of hypermutation in vivo by altering the relative activity of error-prone DNA repair pathways. We analyzed the humoral response and the hypermutation process in mice whose B cells express reduced levels of the Chk1 protein. We found that Chk1 heterozygosity limits the accumulation of mutations in the immunoglobulin loci, likely by impacting on the survival of B cells as they accumulate DNA damage. Nevertheless, we unveiled an unanticipated role for Chk1 downregulation in favoring A/T mutagenesis at the antibody-variable regions during hypermutation. Even though immunoglobulin mutagenesis was found to be reduced, Chk1 signaling attenuation allows for sustained mutagenesis outside the immunoglobulin loci. Our study thus reveals that a proper Chk1 dosage is crucial for adequate somatic hypermutation in B cells.

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Checkpoint kinase 2 is required for efficient immunoglobulin diversification

Cited by 10 publications

References 65 publications

Associations between mutations of the cell cycle checkpoint kinase 2 gene and gastric carcinogenesis

Associations between mutations of the cell cycle checkpoint kinase 2 gene and gastric carcinogenesis

Identification of ultra-rare genetic variants in Pediatric Acute Onset Neuropsychiatric Syndrome (PANS) by exome and whole genome sequencing

Impact of Chk1 dosage on somatic hypermutation in vivo

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