Computational analyses show A-to-G mutations correlate with nascent mRNA hairpins at somatic hypermutation hotspots

Steele, Edward J.; Lindley, Robyn A.; Wen, Jiayu; Weiller, Georg F.

doi:10.1016/j.dnarep.2006.06.002

Cited by 36 publications

(44 citation statements)

References 72 publications

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“…ADAR1 selectively edits two adenosines to inosines in serotonin 2C receptor pre-mRNA (45), and this substrate specificity is the same as for polymerase-copying off a DNA template, which mutates adenosine preferentially when preceded by adenosine or thymidine. Furthermore, the recent report demonstrated the strong statistical association between quantitative patterns of dsRNA secondary structure and adenosine to guanosine mutation spectrum in variable regions of rearranged Ig genes, providing evidence of a link between SHM and adenosine to inosine RNA editing (53). This implies that an RNA editing step could play a significant role in induction of SHM and that a physiologic level of ADAR1 in association with AID may be one of mutators for A-T targeted SHM in GC B cells at their late differentiation phase.…”

Section: Discussionmentioning

confidence: 99%

ADAR1 Protein Induces Adenosine-targeted DNA Mutations in Senescent Bcl6 Gene-deficient Cells

Tsuruoka

Arima

Yoshida

et al. 2013

Journal of Biological Chemistry

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Background: Bcl6 is a potent inhibitor of cell senescence, and somatic mutations accumulate in senescent cells. Results: Mutation frequencies in senescent Bcl6-deficient cells were higher than senescent wild-type cells, and ADAR1 is overexpressed in Bcl6-deficient cells. Conclusion: Bcl6 negatively regulates ADAR1 expression, and ADAR1 overexpression induces adenosine-targeted DNA mutations. Significance: Bcl6 may protect senescent cells from accumulation of somatic mutations.

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Section: Discussionmentioning

confidence: 99%

ADAR1 Protein Induces Adenosine-targeted DNA Mutations in Senescent Bcl6 Gene-deficient Cells

Tsuruoka

Arima

Yoshida

et al. 2013

Journal of Biological Chemistry

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“…It is possible to draw an important implication from this work: If >98% of the genome is transcribed and if the major genome wide strand-biased SNP signature is of A-to-G exceeding T-to-C in transcribed regions [35] this could suggest reverse transcriptase-mediated fixation of RNA editing mutations [36,37 and below] across the genome. A controversial implication from these propositions therefore is that perhaps ≥98% of the human genomic DNA sequence may have passed through an RNA intermediate at some point during evolution.…”

Section: Polak and Arndt Genome-wide Snp Analysesmentioning

confidence: 99%

“…The first component of the genome-wide SNP signature, A-to-G >> T-to-C, is also the defining strand bias of somatic hypermutation (SHM) of immunoglobulin (Ig) genes [36,37]. It is best now understood as the signature of RNA editing events copied back into DNA by cellular reverse transcription.…”

Section: Changing Views On the Origin Of Snpsmentioning

confidence: 99%

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Genesis of ancestral haplotypes: RNA modifications and reverse transcription–mediated polymorphisms

et al. 2011

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how mutations in newly synthesized RNA might be copied back to DNA thus accounting for some of the genome-wide strand biases (e.g. the A-to-G vs T-to-C component of the strand biased spectrum). We hypothesize that the genesis of PFBs and extended AHs occurs during mutagenic episodes in evolution (e.g. retroviral infections) and that many of the critical DNA sequence diversifying events occur first at the RNA level e.g. recombination between RNA strings resulting in tandem and dispersed RNA duplications (retroduplications), RNA mutations via adenosine-to-inosine pre-mRNA editing events as well as error prone RNA synthesis. These are then copied back into DNA by a cellular reverse transcription (RT) process (also likely to be error-prone) we have called "RTmediated long DNA conversion" (RT-LDC). Finally we suggest that all these activities and others can be envisaged as being brought physically under the umbrella of special sites in the nucleus involved in transcription known as "Transcription Factories" (TF).

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“…Other workers in the field have speculated about whether the sense transcript itself plays some role in targeting AID to hotspots for mutation within the V region. For example, it has been suggested that stem-loop-like structures in the nascent RNA could result in transcriptional pausing or affect the targeting of AID in some other way, increasing the likelihood of mutations at particular locations (19,20), and this could equally apply to the antisense transcript. It is also possible that the two nascent RNAs could interact with each other (21).…”

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confidence: 99%

Does antisense make sense of AID targeting?

Roa

Kuang

Scharff

2008

Proc. Natl. Acad. Sci. U.S.A.

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V ertebrates make high-affinity antibodies to protect themselves against pathogenic organisms and their products. The generation of these antibodies requires the highly mutagenic enzyme activation-induced cytidine deaminase (AID) (1). AID deaminates dC to dU in ssDNA, and this mutation recruits additional error-prone repair to carry out somatic hypermutation (SHM) of the antibody variable (V) regions that encode the antigen-binding site, and class switch recombination (CSR), which allows those antigen binding sites to be expressed with different constant regions that mediate effector functions. However, it is still unclear how the genomic instability that is initiated by AID is restricted to only discrete parts of the Ig genes but spares the rest of the genome (2-4). In this issue of PNAS, Perlot et al. (5) provide a partial answer to this puzzle by identifying both sense and antisense transcripts of the V and switch (S) regions, both of which are targeted for mutation by AID; but they find only sense transcripts of the constant (C ) region, which is not targeted by AID (Fig. 1).The finding of antisense transcripts of the V and S regions in primary murine B cells is important because it addresses the unsolved problem of why both the lower (transcribed) and the upper (nontranscribed) strands of the V and S region DNA are highly mutated in mice and humans (6). This has been confusing because biochemical studies with semipurified AID (3, 4) and experiments in which AID was expressed in bacterial cells (7) have found AIDinduced mutations mostly on the upper strand of the targeted DNA. This suggested that something like the large transcription apparatus was protecting the lower strand, whereas the upper strand was accessible to AID ( Fig. 1). A number of explanations have been proposed for why both strands of the V and S regions are mutated in vivo, but not in vitro, such as differences between the mammalian and the bacterial RNA polymerases used in vitro (4), the accessibility of both strands in the supercoiled DNA at the edges of the transcription bubble (8), or ssDNA-binding replication protein A (RPA) participating with AID in mutation (4). Antisense transcription of the V and S regions provides an attractive, although not exclusive, alternative.Antisense transcripts had previously been observed in the V region of a human BurkittЈs lymphoma cell line (9), in S regions within the context of chromosomal translocations (10-12), and in pro-B cells during V(D)J recombination (13), but Perlot et al. (5) are the first to identify such transcripts from a rearranged V region in primary B cells. In the S regions, transcription of the C rich lower strand results in R-loops, where the very G rich nascent RNA hybridizes the template strand and prevents AID action while leaving the upper strand single stranded and accessible to AID (14). However, the G:C content of the V region does not predispose it to R-loop formation, and R-loops have not been found there.There is a considerable body of data that suggests that high rates o...

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Computational analyses show A-to-G mutations correlate with nascent mRNA hairpins at somatic hypermutation hotspots

Cited by 36 publications

References 72 publications

ADAR1 Protein Induces Adenosine-targeted DNA Mutations in Senescent Bcl6 Gene-deficient Cells

ADAR1 Protein Induces Adenosine-targeted DNA Mutations in Senescent Bcl6 Gene-deficient Cells

Genesis of ancestral haplotypes: RNA modifications and reverse transcription–mediated polymorphisms

Does antisense make sense of AID targeting?

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