Recently, immunoglobulins （Igs） were unexpectedly found to be expressed in epithelial cancers. Immunoglobulin class switching or class switch recombination （CSR） is a natural biological process that alters a B cel...Recently, immunoglobulins （Igs） were unexpectedly found to be expressed in epithelial cancers. Immunoglobulin class switching or class switch recombination （CSR） is a natural biological process that alters a B cell＇s production of antibodies （immunoglobulins） from one class to another. However, the mechanism of CSR of Iggenes in cancer is still unknown. Here, we confirmed by detecting the hallmark of CSR that the Iga gene in cancer underwent CSR. Then we focused on activation-induced cytidine deaminase （AID）, a crucial factor for initiating CSR. Further studies using tumor necrosis factor （TNF）-α stimulation and specific inhibitor of NF-KB revealed that TNF-α could increase AID expression through NF-κB signaling. Finally, we demonstrated that AID could co-localize with protein kinase A and bind to the switching （Sα） region of the Igα gene. Overexpression of AID obviously enhanced Igα heavy chain expression and its binding ability to the Sa region. These findings indicated that TNF-α-induced AID expression is involved with CSR in cancer.展开更多
DIS3 is the main catalytic subunit of the nuclear RNA exosome,a complex playing a crucial role in RNA processing and the degradation of various noncoding RNA substrates.In mice,DIS3 is essential for genomic rearrangem...DIS3 is the main catalytic subunit of the nuclear RNA exosome,a complex playing a crucial role in RNA processing and the degradation of various noncoding RNA substrates.In mice,DIS3 is essential for genomic rearrangements during B cell development,but its role in terminal plasma cell(PC)differentiation has not been explored.Although DIS3 gene alterations are frequent in multiple myeloma(MM),a PC malignancy,their molecular impact remains poorly understood.In this study,we developed an antisense oligonucleotide strategy to knock down DIS3 expression in a well-characterized model of human PC differentiation.Reducing DIS3 expression systematically led to decreased B cell proliferation and impaired PC differentiation with lower levels of switched immunoglobulin secretion.Transcriptome analyses confirmed alterations in the proliferation and differentiation programs,alongside an accumulation of noncoding RNAs.Notably,centromere-associated noncoding RNAs were highly sensitive to DIS3 activity,and their accumulation in DIS3-deficient cells,either as transcripts or DNA-associated RNAs,correlated with the mislocalization of the centromere-specific histone variant CENP-A.We finally observed reduced physiological DNA recombination and somatic hypermutation but increased genomic instability in DIS3-deficient cells,in agreement with the higher levels of IGH translocations observed in our large cohort of DIS3-mutant MM patients.Together,these results underscore the essential role of DIS3 in regulating B cell proliferation,DNA recombination,and physiological or malignant PC differentiation in humans.展开更多
Activation-induced deaminase （AID） initiates the secondary antibody diversification process in B lymphocytes. In mammalian B cells, this process includes somatic hypermutation （SHM） and class switch recombination ...Activation-induced deaminase （AID） initiates the secondary antibody diversification process in B lymphocytes. In mammalian B cells, this process includes somatic hypermutation （SHM） and class switch recombination （CSR）, both of which require AID. AID induces U：G mismatch lesions in DNA that are subsequently converted into point mutations or DNA double stranded breaks during SHM/CSR. In a physiological context, AID targets immunogiobulin （Ig） loci to mediate SHM/CSR. However, recent studies reveal genome-wide access of AID to numerous non-Ig loci. Thus, AID poses a threat to the genome of B cells if AID-initiated DNA lesions cannot be properly repaired. In this review, we focus on the molecular mechanisms that regulate the specificity of AID targeting and the repair pathways responsible for processing AID-initiated DNA lesions.展开更多
文摘Recently, immunoglobulins （Igs） were unexpectedly found to be expressed in epithelial cancers. Immunoglobulin class switching or class switch recombination （CSR） is a natural biological process that alters a B cell＇s production of antibodies （immunoglobulins） from one class to another. However, the mechanism of CSR of Iggenes in cancer is still unknown. Here, we confirmed by detecting the hallmark of CSR that the Iga gene in cancer underwent CSR. Then we focused on activation-induced cytidine deaminase （AID）, a crucial factor for initiating CSR. Further studies using tumor necrosis factor （TNF）-α stimulation and specific inhibitor of NF-KB revealed that TNF-α could increase AID expression through NF-κB signaling. Finally, we demonstrated that AID could co-localize with protein kinase A and bind to the switching （Sα） region of the Igα gene. Overexpression of AID obviously enhanced Igα heavy chain expression and its binding ability to the Sa region. These findings indicated that TNF-α-induced AID expression is involved with CSR in cancer.
基金supported by the following grants:Agence nationale de la recherche(ANR)grant R23192NNInstitut national du cancer(INCa)grant PLBIO22-217+2 种基金Association pour la Recherche sur le Cancer(ARC)grant ARCPJA2021060003753 and PRTK 2021-025Ligue contre le cancer Grand-OuestAllocations de Recherche Doctorale région Bretagne/Inserm PhD fellowship.
文摘DIS3 is the main catalytic subunit of the nuclear RNA exosome,a complex playing a crucial role in RNA processing and the degradation of various noncoding RNA substrates.In mice,DIS3 is essential for genomic rearrangements during B cell development,but its role in terminal plasma cell(PC)differentiation has not been explored.Although DIS3 gene alterations are frequent in multiple myeloma(MM),a PC malignancy,their molecular impact remains poorly understood.In this study,we developed an antisense oligonucleotide strategy to knock down DIS3 expression in a well-characterized model of human PC differentiation.Reducing DIS3 expression systematically led to decreased B cell proliferation and impaired PC differentiation with lower levels of switched immunoglobulin secretion.Transcriptome analyses confirmed alterations in the proliferation and differentiation programs,alongside an accumulation of noncoding RNAs.Notably,centromere-associated noncoding RNAs were highly sensitive to DIS3 activity,and their accumulation in DIS3-deficient cells,either as transcripts or DNA-associated RNAs,correlated with the mislocalization of the centromere-specific histone variant CENP-A.We finally observed reduced physiological DNA recombination and somatic hypermutation but increased genomic instability in DIS3-deficient cells,in agreement with the higher levels of IGH translocations observed in our large cohort of DIS3-mutant MM patients.Together,these results underscore the essential role of DIS3 in regulating B cell proliferation,DNA recombination,and physiological or malignant PC differentiation in humans.
文摘Activation-induced deaminase （AID） initiates the secondary antibody diversification process in B lymphocytes. In mammalian B cells, this process includes somatic hypermutation （SHM） and class switch recombination （CSR）, both of which require AID. AID induces U：G mismatch lesions in DNA that are subsequently converted into point mutations or DNA double stranded breaks during SHM/CSR. In a physiological context, AID targets immunogiobulin （Ig） loci to mediate SHM/CSR. However, recent studies reveal genome-wide access of AID to numerous non-Ig loci. Thus, AID poses a threat to the genome of B cells if AID-initiated DNA lesions cannot be properly repaired. In this review, we focus on the molecular mechanisms that regulate the specificity of AID targeting and the repair pathways responsible for processing AID-initiated DNA lesions.
