Changes in RNA polymerase II progression influence somatic hypermutation of Ig-related genes by AID

Kodgire, Prashant; Mukkawar, Priyanka; Ratnam, Sarayu; Martin, Terence E.; Storb, Ursula

doi:10.1084/jem.20121523

Cited by 38 publications

(33 citation statements)

References 46 publications

(74 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…One aspect of SHM that merits brief discussion here is the mechanism by which AID, an exclusively single-stranded (ss) DNA-specific cytidine deaminase, accesses the variable region exons. One possibility is that transcription promotes negative supercoiling of DNA upstream of the elongating RNA polymerase, thus creating DNA topology conducive for AID binding (Kodgire, Mukkawar, Ratnam, Martin, &Storb, 2013; Shen &Storb, 2004). Another, not necessarily mutually exclusive, proposal is that the ssDNA binding protein r eplication p rotein A (RPA), which interacts with AID, stabilizes ssDNA bubbles within transcribed variable region exons, allowing AID-mediated deamination to facilitate SHM (Chaudhuri, Khuong, & Alt, et al, 2004).…”

Section: Overview Of Genomic Alterations In B Cellsmentioning

confidence: 99%

Regulation of Immunoglobulin Class-Switch Recombination

Matthews

Zheng

DiMenna

et al. 2014

Advances in Immunology

125

View full text Add to dashboard Cite

Upon encountering antigens, mature IgM-positive B lymphocytes undergo class-switch recombination (CSR) wherein exons encoding the default Cμ constant coding gene segment of the immunoglobulin (Ig) heavy-chain (Igh) locus are excised and replaced with a new constant gene segment (referred to as “Ch genes”, e.g., Cγ, Cε, or Cα). The B cell thereby changes from expressing IgM to one producing IgG, IgE, or IgA, with each antibody isotype having a different effector function during an immune reaction. CSR is a DNA deletional-recombination reaction that proceeds through the generation of DNA double-strand breaks (DSBs) in repetitive switch (S) sequences preceding each Ch gene and is completed by end-joining between donor Sμ and acceptor S regions. CSR is a multistep reaction requiring transcription through S regions, the DNA cytidine deaminase AID, and the participation of several general DNA repair pathways including base excision repair, mismatch repair, and classical nonhomologous end-joining. In this review, we discuss our current understanding of how transcription through S regions generates substrates for AID-mediated deamination and how AID participates not only in the initiation of CSR but also in the conversion of deaminated residues into DSBs. Additionally, we review the multiple processes that regulate AID expression and facilitate its recruitment specifically to the Ig loci, and how deregulation of AID specificity leads to oncogenic translocations. Finally, we summarize recent data on the potential role of AID in the maintenance of the pluripotent stem cell state during epigenetic reprogramming.

show abstract

Section: Overview Of Genomic Alterations In B Cellsmentioning

confidence: 99%

Regulation of Immunoglobulin Class-Switch Recombination

Matthews

Zheng

DiMenna

et al. 2014

Advances in Immunology

125

View full text Add to dashboard Cite

show abstract

“…This in turn would create a preponderance of premature transcription termination leading to RNA exosome recruitment for the resolution of arrested transcription complexes. In fact, artificially inducing premature transcriptional arrest at an Ig locus through targeted insertion of a transcription termination element leads to enhanced hypermutation in the upstream region proximal to the site of transcription termination (Kodgire et al, 2013). An abundance of distinct transcription obstacles, particularly at IgH , may therefore create a synergistic effect with respect to premature transcription termination, which may in turn underlie the “targeting” phenomenon of AID towards Ig loci.…”

Section: Transcription Stalling As a Mechanism Of Rna Exosome Medimentioning

confidence: 99%

RNA Exosome Regulates AID DNA Mutator Activity in the B Cell Genome

Pefanis

Basu

2015

Advances in Immunology

View full text Add to dashboard Cite

The immunoglobulin diversification processes of somatic hypermutation and class switch recombination critically rely on transcription coupled targeting of AID to Ig loci in activated B lymphocytes. AID catalyzes deamination of cytidine deoxynucleotides on exposed single stranded DNA. In addition to driving immunoglobulin diversity, promiscuous targeting of AID mutagenic activity poses a deleterious threat to genomic stability. Recent genome-wide studies have uncovered pervasive AID activity throughout the B cell genome. It is increasingly apparent that AID activity is frequently targeted to genomic loci undergoing early transcription termination where RNA exosome promotes the resolution of stalled transcription complexes via co-transcriptional RNA degradation mechanisms. Here we review aspects and consequences of eukaryotic transcription that lead to early termination, RNA exosome recruitment, and ultimately targeting of AID mutagenic activity.

show abstract

“…However, it remains unclear which aspects of transcription regulate SHM and through what mechanisms. A recent study knocked-in a transcription terminator into an Ig gene V region in the DT40 chicken B cell line [83]. The knock-in human β-globin terminator reduced mutations downstream of the poly(A) signal, which was accompanied by efficient inhibition of downstream transcription [83].…”

Section: Cis Regulatory Elements In Shm Targetingmentioning

confidence: 99%

“…A recent study knocked-in a transcription terminator into an Ig gene V region in the DT40 chicken B cell line [83]. The knock-in human β-globin terminator reduced mutations downstream of the poly(A) signal, which was accompanied by efficient inhibition of downstream transcription [83]. These data suggest that target DNA sequences gain better access to AID when RNAP II is in the elongating rather than terminating mode [83].…”

Section: Cis Regulatory Elements In Shm Targetingmentioning

confidence: 99%

“…The knock-in human β-globin terminator reduced mutations downstream of the poly(A) signal, which was accompanied by efficient inhibition of downstream transcription [83]. These data suggest that target DNA sequences gain better access to AID when RNAP II is in the elongating rather than terminating mode [83]. Transcription may also guide AID in targeting SHM to Ig genes via regulating histone-exchanging dynamics at these loci [84].…”

Section: Cis Regulatory Elements In Shm Targetingmentioning

confidence: 99%

See 1 more Smart Citation

Generation and repair of AID-initiated DNA lesions in B lymphocytes

Chen

Wang

2014

Front. Med.

View full text Add to dashboard Cite

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 immunoglobulin (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.

show abstract

Changes in RNA polymerase II progression influence somatic hypermutation of Ig-related genes by AID

Abstract: Ongoing transcription of the Ig gene coupled with temporary pausing within the targeted region facilitates somatic hypermutation.

Cited by 38 publications

References 46 publications

Regulation of Immunoglobulin Class-Switch Recombination

Regulation of Immunoglobulin Class-Switch Recombination

RNA Exosome Regulates AID DNA Mutator Activity in the B Cell Genome

Generation and repair of AID-initiated DNA lesions in B lymphocytes

Contact Info

Product

Resources

About