Human activation-induced cytidine deaminase causes transcription-dependent, strand-biased C to U deaminations

Sohail, Anjum; Klapacz, Joanna; Samaranayake, Mala; Ullah, Asad; Bhagwat, Ashok S.

doi:10.1093/nar/gkg464

Cited by 255 publications

(244 citation statements)

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“…In the E. coli studies, a specific increase in C3T mutations has been attributed to enhanced deamination of cytosines located on the NTS, presumably because of the transcription-associated single-stranded character of this strand (3). It has recently been demonstrated that cytosines on the NTS are preferred targets for AID, a deaminase involved in initiating somatic hypermutation of immunoglobulin genes (35,37). In addition to enhancing BS, an increase in large deletions that inactivate a plasmid-based lacZ target has been reported when high levels of transcription oppose the direction of replication fork movement in E. coli (40).…”

Section: Discussionmentioning

confidence: 99%

Identification of a Distinctive Mutation Spectrum Associated with High Levels of Transcription in Yeast

Lippert

Freedman

Barber

et al. 2004

Molecular and Cellular Biology

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High levels of transcription are associated with increased mutation rates in Saccharomyces cerevisiae, a phenomenon termed transcription-associated mutation (TAM). To obtain insight into the mechanism of TAM, we obtained LYS2 forward mutation spectra under low-versus high-transcription conditions in which LYS2 was expressed from either the low-level pLYS2 promoter or the strong pGAL1-10 promoter, respectively. Because of the large size of the LYS2 locus, forward mutations first were mapped to specific LYS2 subregions, and then those mutations that occurred within a defined 736-bp target region were sequenced. In the low-transcription strain base substitutions comprised the majority (64%) of mutations, whereas short insertion-deletion mutations predominated (56%) in the high-transcription strain. Most notably, deletions of 2 nucleotides (nt) comprised 21% of the mutations in the high-transcription strain, and these events occurred predominantly at 5 -(G/C)AAA-3 sites. No ؊2 events were present in the low-transcription spectrum, thus identifying 2-nt deletions as a unique mutational signature for TAM.Transcription influences genomic stability in a complex manner by affecting DNA repair, recombination, mutagenesis, and chromatin structure (reviewed in references 1 and 31). In the subpathway of nucleotide excision repair known as transcription-coupled repair, for example, the encounter of RNA polymerase (Pol) with a transcription-blocking lesion on the transcribed strand specifically triggers repair of the damage, resulting in more efficient repair of lesions on the transcribed strand than on the nontranscribed strand (16). In addition to promoting strand-specific repair, high levels of transcription have been shown to elevate recombination rates in Saccharomyces cerevisiae (33,36,39,41), Schizosaccharomyces pombe (15), and mammalian cells (34). Finally, increased transcription has been shown to stimulate spontaneous mutagenesis in Escherichia coli (3,24,44) and bacteriophage T7 (4) and to enhance deletions within an E. coli plasmid target (40). In S. cerevisiae, Datta and Jinks-Robertson demonstrated previously that an increased transcription level likewise stimulates spontaneous mutation rates, a phenomenon termed transcriptionassociated mutation, or TAM (8). Specifically, reversion of the lys2⌬Bgl frameshift allele and forward mutation at the LYS2 locus increased 35-and 10-fold, respectively, in response to transcriptional induction from the pGAL1-10 promoter. Whereas the genetic requirements and underlying mechanisms of transcription-coupled repair (16, 38) and transcription-associated recombination are becoming clearer (11,12,21), the mechanism of TAM is still poorly understood.The genetic requirements and mutation spectrum of TAM have been characterized in yeast strains using lys2⌬Bgl, a ϩ4 frameshift allele that reverts by acquisition of compensatory Ϫ1 frameshift mutations. In the high-transcription strain, 70% of the reversion mutations required Rev3p, a component of the translesion synthesis DNA Pol , sugg...

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Section: Discussionmentioning

confidence: 99%

Identification of a Distinctive Mutation Spectrum Associated with High Levels of Transcription in Yeast

Lippert

Freedman

Barber

et al. 2004

Molecular and Cellular Biology

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“…Transcription bubbles, structures in which ssDNA is exposed due to helicase activity of the RNA polymerase complex, are known targets of AID [65][66][67][68] and represent a likely source of mutations in coding regions if replication occurs before repair of dU.…”

Section: Availability Of Ssdna Substratementioning

confidence: 99%

APOBEC3 genes: retroviral restriction factors to cancer drivers

Henderson

Fenton

2015

Trends in Molecular Medicine

106

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Abstract:The APOBEC3 cytosine deaminases play key roles in innate immunity through their ability to mutagenize viral DNA and restrict viral replication. Now recent advances in cancer genomics together with biochemical characterization of the APOBEC3 enzymes have implicated at least two family members in somatic mutagenesis during tumor development. Here we review the evidence linking these enzymes to carcinogenesis and highlight key questions, including the potential mechanisms that misdirect APOBEC3 activity to the host genome, the links to viral infection, and the association between a common APOBEC3 polymorphism and cancer risk. Powered by Editorial Manager® and ProduXion Manager® from Aries Systems CorporationHenderson and Fenton: highlights AbstractThe APOBEC3 cytosine deaminases play key roles in innate immunity through their

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Section: Transitions From Innate To Adaptive Immunitymentioning

confidence: 99%

“…So, the appearance of a class-switch reaction was dependent on the evolution of switch-region sequences. AID-like and uracil-DNA glycosylase (UNG)-like proteins, which are involved in these processes, had ancient origins, co-evolving with innate immune antiviral defences [49][50][51] .Over time, V-gene duplication and germline substitutions, which were focused in COMPLEMENTARITY-DETERMINING REGION 1 (CDR1) and CDR2, coupled with combinatorial joining, imparted a considerable selective advantage in terms of deriving receptor diversity. Somatic hypermutation of immunoglobulin genes, which is a central feature of BCR maturation, occurs in the earliest extant jawed vertebrates -the cartilaginous fish 52,53 -and might be an accentuation of a genome-wide process 54,55 .…”

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confidence: 99%

Reconstructing immune phylogeny: new perspectives

2005

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Numerous studies of the mammalian immune system have begun to uncover profound interrelationships, as well as fundamental differences, between the adaptive and innate systems of immune recognition. Coincident with these investigations, the increasing experimental accessibility of non-mammalian jawed vertebrates, jawless vertebrates, protochordates and invertebrates has provided intriguing new information regarding the likely patterns of emergence of immune-related molecules during metazoan phylogeny, as well as the evolution of alternative mechanisms for receptor diversification. Such findings blur traditional distinctions between adaptive and innate immunity and emphasize that, throughout evolution, the immune system has used a remarkably extensive variety of solutions to meet fundamentally similar requirements for host protection.The evolutionary development of the METAZOANS was associated with the diversification of a wide range of specialized cell-surface molecules that mediate key metabolic processes, as well as provide crucial contact interfaces and carry out a broad range of other essential functions. It is not unexpected that some of these molecules also came to function as barriers to pathogenic invasion and, in doing so, began to carry out dedicated innate immune protective functions. Whereas the simplest form of protection, barrier formation, is essentially mechanical in nature, relentless pressure from genetic variation in pathogens probably drove the evolution of such innate immune protective molecules towards diversification and, in parallel, towards integration of signalling pathways to regulate cellular responses to external stimulation. However, despite the sophistication that such innate immune mediators achieved over time, their biological complexity, by definition, would be limited by genome space, so with increasing complexity of body plan and/or increasing pathogen sophistication, they could be overwhelmed. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptMore than 500 million years ago, a TRANSPOSITION event, probably involving a recombinationactivating gene (RAG)-bearing element, might have given rise to the predecessors of the rearranging antigen-binding receptors of the jawed vertebrates, which encompass the vertebrate radiations that extend from the cartilaginous fish through to humans. This is considered the defining point in the emergence of RAG-mediated (conventional) adaptive immunity 1,2 , which has evolved to create a mechanism for deriving almost limitless variation from very few genes. Studies in traditional and non-traditional animal models, such as sharks, bony fish and birds, have brought this event and its ramifications for host defence into sharper focus. We can now predict much about how these rearranging antigenbinding receptors probably arose, what alternative pathways of immune-receptor gene evolution have occurred, what relationships exist between B-and T-cell-mediated immunity and natural killer (NK)-cell function, how complex immune ...

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Human activation-induced cytidine deaminase causes transcription-dependent, strand-biased C to U deaminations

Cited by 255 publications

References 28 publications

Identification of a Distinctive Mutation Spectrum Associated with High Levels of Transcription in Yeast

Identification of a Distinctive Mutation Spectrum Associated with High Levels of Transcription in Yeast

APOBEC3 genes: retroviral restriction factors to cancer drivers

Reconstructing immune phylogeny: new perspectives

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