R Loops in the Regulation of Antibody Gene Diversification

Pavri, Rushad

doi:10.3390/genes8060154

Cited by 30 publications

(19 citation statements)

References 57 publications

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“…A number of DNA repair proteins have been implicated in the SH and CSR processes. Their relevance in SH and CSR has been inferred from the phenotypes of their gene knockouts (7,(30)(31)(32), but there are little data addressing if the importance of an implicated protein is through a direct participation of the protein at the sites of SH and CSR or, alternatively, if the phenotype of the mutant is indirect through an effect on an upstream process of importance for SH and CSR. In the current study, we show by PLA and co-IP that a high number of proteins implicated in SH and CSR, including BER proteins, MMR proteins, AID, the DNA clamp protein PCNA, E2A, and PAX5 transcription factors involved in targeting of CSR/SH, DNA polymerase d, DNA polymerase h, and other error-prone translesion DNA polymerases, assemble together during the SH and CSR processes.…”

Section: Discussionmentioning

confidence: 99%

Regulation of the DNA Repair Complex during Somatic Hypermutation and Class-Switch Recombination

Kumar

Priya

Ahmed

et al. 2018

The Journal of Immunology

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B lymphocytes optimize Ab responses by somatic hypermutation (SH), which introduces point mutations in the variable regions of the Ab genes and by class-switch recombination (CSR), which changes the expressed C region exon of the IgH. These Ab diversification processes are initiated by the deaminating enzyme activation-induced cytidine deaminase followed by many DNA repair enzymes, ultimately leading to deletions and a high mutation rate in the Ab genes, whereas DNA lesions made by activation-induced cytidine deaminase are repaired with low error rate on most other genes. This indicates an advanced regulation of DNA repair. In this study, we show that initiation of Ab diversification in B lymphocytes of mouse spleen leads to formation of a complex between many proteins in DNA repair. We show also that BCR activation, which signals the end of successful SH, reduces interactions between some proteins in the complex and increases other interactions in the complex with varying kinetics. Furthermore, we show increased localization of SH- and CSR-coupled proteins on switch regions of the locus upon initiation of SH/CSR and differential changes in the localization upon BCR signaling, which terminates SH. These findings provide early evidence for a DNA repair complex or complexes that may be of functional significance for carrying out essential roles in SH and/or CSR in B cells.

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Section: Discussionmentioning

confidence: 99%

Regulation of the DNA Repair Complex during Somatic Hypermutation and Class-Switch Recombination

Kumar

Priya

Ahmed

et al. 2018

The Journal of Immunology

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“…Remarkably, the DSB repair processes (mainly C-NHEJ) are critical for the diversity of T and B cells and for an effective adaptive immunity, such as the V(D)J recombination, class-switch recombination and somatic hypermutation (SHM) [100,101]. Of note, R loops have been linked to the regulation of antibody gene diversification [102] and class switch recombination (CSR), which results in the production of the various antibody isotypes that serve crucial effector functions during the humoral immune response [103,104]. R loops form during transcription of switch recombination sequences in vitro and in vivo, and there is solid evidence that R loops are required for efficient class switching.…”

Section: Dna Damage Signalling and Processing Of Double-strand Endsmentioning

confidence: 99%

Replication Stress, DNA Damage, Inflammatory Cytokines and Innate Immune Response

Ragu

Matos-Rodrigues

Lopez

2020

Genes

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Complete and accurate DNA replication is essential to genome stability maintenance during cellular division. However, cells are routinely challenged by endogenous as well as exogenous agents that threaten DNA stability. DNA breaks and the activation of the DNA damage response (DDR) arising from endogenous replication stress have been observed at pre-or early stages of oncogenesis and senescence. Proper detection and signalling of DNA damage are essential for the autonomous cellular response in which the DDR regulates cell cycle progression and controls the repair machinery. In addition to this autonomous cellular response, replicative stress changes the cellular microenvironment, activating the innate immune response that enables the organism to protect itself against the proliferation of damaged cells. Thereby, the recent descriptions of the mechanisms of the pro-inflammatory response activation after replication stress, DNA damage and DDR defects constitute important conceptual novelties. Here, we review the links of replication, DNA damage and DDR defects to innate immunity activation by pro-inflammatory paracrine effects, highlighting the implications for human syndromes and immunotherapies.Genes 2020, 11, 409 2 of 26 formed when nascent transcripts re-anneal to their template DNA, displacing the non-template strand as single-stranded DNA (ssDNA) [12]. Elevated R-loop levels cause DNA damage and genome instability. The loss of RNA processing and regulatory factors increases R-loop levels, causing R-loop dependent DNA damage in eukaryotic cells [13][14][15][16].DNA breaks and activation of the DNA damage response (DDR), arising from endogenous replication stress, have been observed at early or precancerous stages, and adaptation to replication stress plays an important role in tumour development [17][18][19][20]. The DDR protects genome stability through the precise coordination of a network of pathways, ensuring faithful transmission of genetic material, including DNA replication, repair and recombination, cell cycle checkpoint and chromosome segregation. Ultimately, these autonomous cell responses induce senescence or cell death [21][22][23][24][25]. All these processes prevent the proliferation of cells bearing DNA damage and/or genetic rearrangements. In agreement, syndromes caused by mutations in DDR and/or DNA repair factors are often associated with high genetic instability, cancer predisposition and premature ageing [24,[26][27][28]. In addition to these cell-autonomous responses, protective process(es) also act at the organism level. Such mechanism(s) involve the modification of the cellular microenvironment and ultimately the activation of innate immunity.The inflammatory response is a universal cell-intrinsic response to infections or tissue damage. Inflammation, which is triggered when innate immune cells detect infection, for example, eliminates the initial cause of cell injury, clears out necrotic cells and tissues damaged from the original insult and from the inflammatory process, and initiates ...

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Section: Introductionmentioning

confidence: 99%

“…The mechanism by which AID is recruited to the Igh locus during CSR is intricately linked to germline transcription ( Pavri, 2017 ; Yewdell and Chaudhuri, 2017 ). Each of the C h genes is configured as individual germline transcription units composed of a cytokine- and activator-inducible promoter, an intervening I exon, an intronic S region, and C h exons ( Pavri, 2017 ; Yewdell and Chaudhuri, 2017 ). It is generally believed that transcription generates DNA structures, such as G quadruplexes and R loops, to facilitate AID recruitment and deamination ( Chaudhuri et al, 2003 ; Duquette et al, 2005 ; Qiao et al, 2017 ; Yu and Lieber, 2003 ).…”

Section: Introductionmentioning

confidence: 99%