Roles of G4-DNA and G4-RNA in Class Switch Recombination and Additional Regulations in B-Lymphocytes

Dézé, Ophélie; Laffleur, Brice; Cogné, Michel

doi:10.3390/molecules28031159

Cited by 6 publications

(4 citation statements)

References 183 publications

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“…These methylation and oxidation patterns result in G4 sequence preservation. In addition, cytosine deamination has been shown to have important roles in the G4 structure, including a destabilization in telomeres [126] and a class switch recombination in mature B cells [127].…”

Section: Discussionmentioning

confidence: 99%

Analysis of Nucleotide Variations in Human G-Quadruplex Forming Regions Associated with Disease States

Neupane,

Chariker,

Rouchka

2023

Genes

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While the role of G quadruplex (G4) structures has been identified in cancers and metabolic disorders, single nucleotide variations (SNVs) and their effect on G4s in disease contexts have not been extensively studied. The COSMIC and CLINVAR databases were used to detect SNVs present in G4s to identify sequence level changes and their effect on the alteration of the G4 secondary structure. A total of 37,515 G4 SNVs in the COSMIC database and 2378 in CLINVAR were identified. Of those, 7236 COSMIC (19.3%) and 457 (19%) of the CLINVAR variants result in G4 loss, while 2728 (COSMIC) and 129 (CLINVAR) SNVs gain a G4 structure. The remaining variants potentially affect the folding energy without affecting the presence of a G4. Analysis of mutational patterns in the G4 structure shows a higher selective pressure (3-fold) in the coding region on the template strand compared to the reverse strand. At the same time, an equal proportion of SNVs were observed among intronic, promoter, and enhancer regions across strands.

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Section: Discussionmentioning

confidence: 99%

Analysis of Nucleotide Variations in Human G-Quadruplex Forming Regions Associated with Disease States

Neupane,

Chariker,

Rouchka

2023

Genes

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“…There is evidence that AID features an intrinsic preference for G-quadruplex (G4)-containing DNA ( 92 ). G4-DNA structures formed by G-rich sequences present in S regions appear to induce CSR by promoting AID binding ( 93 , 94 ). The binding of AID to the active S region requires the participation of 14-3-3 adaptor proteins ( 95 ) and also involves the recruitment of protein kinase A (PKA) ( 96 ).…”

Section: Mechanism For Generation Of Antibody Diversitymentioning

confidence: 99%

Role of the mechanisms for antibody repertoire diversification in monoclonal light chain deposition disorders: when a friend becomes foe

et al. 2023

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The adaptive immune system of jawed vertebrates generates a highly diverse repertoire of antibodies to meet the antigenic challenges of a constantly evolving biological ecosystem. Most of the diversity is generated by two mechanisms: V(D)J gene recombination and somatic hypermutation (SHM). SHM introduces changes in the variable domain of antibodies, mostly in the regions that form the paratope, yielding antibodies with higher antigen binding affinity. However, antigen recognition is only possible if the antibody folds into a stable functional conformation. Therefore, a key force determining the survival of B cell clones undergoing somatic hypermutation is the ability of the mutated heavy and light chains to efficiently fold and assemble into a functional antibody. The antibody is the structural context where the selection of the somatic mutations occurs, and where both the heavy and light chains benefit from protective mechanisms that counteract the potentially deleterious impact of the changes. However, in patients with monoclonal gammopathies, the proliferating plasma cell clone may overproduce the light chain, which is then secreted into the bloodstream. This places the light chain out of the protective context provided by the quaternary structure of the antibody, increasing the risk of misfolding and aggregation due to destabilizing somatic mutations. Light chain-derived (AL) amyloidosis, light chain deposition disease (LCDD), Fanconi syndrome, and myeloma (cast) nephropathy are a diverse group of diseases derived from the pathologic aggregation of light chains, in which somatic mutations are recognized to play a role. In this review, we address the mechanisms by which somatic mutations promote the misfolding and pathological aggregation of the light chains, with an emphasis on AL amyloidosis. We also analyze the contribution of the variable domain (VL) gene segments and somatic mutations on light chain cytotoxicity, organ tropism, and structure of the AL fibrils. Finally, we analyze the most recent advances in the development of computational algorithms to predict the role of somatic mutations in the cardiotoxicity of amyloidogenic light chains and discuss the challenges and perspectives that this approach faces.

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“…G4s are required for replication initiation [25,26] and high-order chromatin organization [27,28]. In B-cell lineage, G-quadruplexes may form at the IGH locus at (V) variable regions and switch-regions, thereby promoting hypermutation and class-switch recombination [29]. Several studies provide evidence for the association of G-quadruplexes with DNA modifications and function of epigenome [30][31][32].…”

Section: Introductionmentioning

confidence: 99%

G-Quadruplex Forming DNA Sequence Context Is Enriched around Points of Somatic Mutations in a Subset of Multiple Myeloma Patients

Zhuk,

Stepchenkova,

Zotova

et al. 2024

IJMS

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Multiple myeloma (MM) is the second most common hematological malignancy, which remains incurable despite recent advances in treatment strategies. Like other forms of cancer, MM is characterized by genomic instability, caused by defects in DNA repair. Along with mutations in DNA repair genes and genotoxic drugs used to treat MM, non-canonical secondary DNA structures (four-stranded G-quadruplex structures) can affect accumulation of somatic mutations and chromosomal abnormalities in the tumor cells of MM patients. Here, we tested the hypothesis that G-quadruplex structures may influence the distribution of somatic mutations in the tumor cells of MM patients. We sequenced exomes of normal and tumor cells of 11 MM patients and analyzed the data for the presence of G4 context around points of somatic mutations. To identify molecular mechanisms that could affect mutational profile of tumors, we also analyzed mutational signatures in tumor cells as well as germline mutations for the presence of specific SNPs in DNA repair genes or in genes regulating G-quadruplex unwinding. In several patients, we found that sites of somatic mutations are frequently located in regions with G4 context. This pattern correlated with specific germline variants found in these patients. We discuss the possible implications of these variants for mutation accumulation and specificity in MM and propose that the extent of G4 context enrichment around somatic mutation sites may be a novel metric characterizing mutational processes in tumors.

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Roles of G4-DNA and G4-RNA in Class Switch Recombination and Additional Regulations in B-Lymphocytes

Cited by 6 publications

References 183 publications

Analysis of Nucleotide Variations in Human G-Quadruplex Forming Regions Associated with Disease States

Analysis of Nucleotide Variations in Human G-Quadruplex Forming Regions Associated with Disease States

Role of the mechanisms for antibody repertoire diversification in monoclonal light chain deposition disorders: when a friend becomes foe

G-Quadruplex Forming DNA Sequence Context Is Enriched around Points of Somatic Mutations in a Subset of Multiple Myeloma Patients

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