AID binds to transcription-induced structures in c-MYC that map to regions associated with translocation and hypermutation

Duquette, Michelle L.; Pham, Phuong; Goodman, Myron F.; Maizels, Nancy

doi:10.1038/sj.onc.1208746

Cited by 129 publications

(153 citation statements)

References 59 publications

(86 reference statements)

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“…Given that different nucleases, RAG or AID, are responsible for the various IGH cleavage sites, the fact that the JH breakpoints and switch m breakpoints did not differ with respect to their corresponding MYC breakpoint regions is unexpected and may suggest that a third mechanism is responsible for DNA cleavage in MYC; or that RAG and AID may cause cleavage in MYC breakpoint regions equivalently, possibly due to structural attributes of the MYC promoter region (see below). Duquette,19 recently demonstrated that AID targets to G-loops, co-transcriptional RNA: DNA hybrids on the C-rich strand and single-stranded regions and G4 DNA on the G-rich strand. 19 Similar distributions of RAG induced JH and AID induced switch m breakpoints does not necessarily argue against a prominent role of these G-loops.…”

Section: Discussionmentioning

confidence: 99%

“…Duquette,19 recently demonstrated that AID targets to G-loops, co-transcriptional RNA: DNA hybrids on the C-rich strand and single-stranded regions and G4 DNA on the G-rich strand. 19 Similar distributions of RAG induced JH and AID induced switch m breakpoints does not necessarily argue against a prominent role of these G-loops. The clusters on MYC were quite wide and diffuse (560 and 779 bp in a 4555 bp region) compared to three sharply circumscribed peaks (10-15 bp in a region of 150 bp) described previously within Mbr of BCL-2 and attributed to RAG activity.…”

Section: Discussionmentioning

confidence: 99%

“…1,18,19 Sporadic Burkitts lymphoma (sBL) carry the translocation t (8;14). 20,21 Breakpoints on chromosome 14 occur either within the IGH switch regions (Sa, Sg and Sm) or in the joining region (JH).…”

Section: Introductionmentioning

confidence: 99%

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Identification of two distinct MYC breakpoint clusters and their association with various IGH breakpoint regions in the t(8;14) translocations in sporadic Burkitt-lymphoma

et al. 2007

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The chromosomal translocation t(8;14) is the hallmark of Burkitt's-lymphoma (BL) and fuses the proto-oncogene c-MYC to the IGH locus. We analyzed the genomic structure of MYC/ IGH fusions derived from a large series of 78 patients with t(8;14) and asked (i) whether distinct breakpoint clusters exist within the MYC gene and (ii) whether any pairwise association between particular IGH and MYC breakpoints exist. Identification of such associations will help elucidate the etiology of the breaks on the MYC locus. Scan statistic analyses revealed two distinct, but large clusters within c-MYC containing 60/78 (77%) of the breakpoints. Clusters 1 and 2 were 560 and 779 bp in length within a 4555 bp breakpoint cluster region. Breaks within IGH switch l and joining region did not differ with respect to their corresponding MYC breakpoints. However, there was a highly significant correlation between breakpoints 5 0 of MYC cluster 1 and fusions to IGH switch c region and breakpoints downstream of MYC cluster 2 and fusions to IGH switch a region (v 2 -test: Po0.005). Chromatin changes governing choice of IGH-Fc region recombination may parallel changes in the MYC gene 5 0 region chromatin leading to some degree of coordinated ontological specificity in breakpoint location.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Identification of two distinct MYC breakpoint clusters and their association with various IGH breakpoint regions in the t(8;14) translocations in sporadic Burkitt-lymphoma

et al. 2007

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“…Because of its high G content, the NT DNA strand at S regions could be stabilized by the formation of parallel four-stranded G quartets (17,18). Indeed, AID appears to bind specifically to G-loops within transcribed S regions (19) and can deaminate the displaced strand of a transcription-induced R-loop in vitro (20).…”

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confidence: 99%

Activation-induced cytidine deaminase action is strongly stimulated by mutations of the THO complex

Gómez-González

Aguilera

2007

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

103

111

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Activation-induced cytidine deaminase (AID) is a B cell enzyme essential for Ig somatic hypermutation and class switch recombination. AID acts on ssDNA, and switch regions of Ig genes, a target of AID, form R-loops that contain ssDNA. Nevertheless, how AID action is specifically targeted to particular DNA sequences is not clear. Because mutations altering cotranscriptional messenger ribonucleoprotein (mRNP) formation such as those in THO/TREX in yeast promote R-loops, we investigated whether the cotranscriptional assembly of mRNPs could affect AID targeting. Here we show that AID action is transcription-dependent in yeast and that strong and transcription-dependent hypermutation and hyperrecombination are induced by AID if cells are deprived of THO. In these strains AID-induced mutations occurred preferentially at WRC motifs in the nontranscribed DNA strand. We propose that a suboptimal cotranscriptional mRNP assembly at particular DNA regions could play an important role in Ig diversification and genome dynamics.hyperrecombination ͉ hypermutation ͉ messenger ribonucleoprotein biogenesis ͉ R-loops A ctivation-induced cytidine deaminase (AID) is a specific B cell enzyme believed to be responsible for the initiation of somatic hypermutation (SHM) and class switch recombination (CSR) during B cell differentiation (1-3). Many studies have shown that AID acts directly on DNA (4), the natural target for AID action in the variable and switch (S) regions for SHM and CSR, respectively. The specific mechanisms of AID function are still unclear, but evidence suggests that the preferential target of AID may be ssDNA (5, 6). Thus, in vitro experiments have shown that AID deaminates ssDNA and dsDNA that is transcribed (5-7), and transcription has been shown to be required for both SHM and CSR in vivo (8,9).Studies have shown a strand preference for the action of AID during in vitro transcription with AID-induced mutations detected preferentially in the nontranscribed (NT) strand (6,(10)(11)(12). Analysis of the products of SHM in B cells, however, reveals that both DNA strands are mutated (13). Other in vitro studies have shown that AID can deaminate both strands within regions of supercoiled DNA (14) and that the ssDNA-binding replication protein A is required for deamination of SHM targets (15). All of these findings are consistent with the idea that transient formation of ssDNA during transcription facilitates AID action.Along the same line, formation of R-loops during transcription of the S regions has been proposed (16). Such R-loops would possibly provide AID with ssDNA substrates at its target region because there the transcribed (T) strand hybridizes with the nascent RNA and the NT strand is present as ssDNA. Because of its high G content, the NT DNA strand at S regions could be stabilized by the formation of parallel four-stranded G quartets (17, 18). Indeed, AID appears to bind specifically to G-loops within transcribed S regions (19) and can deaminate the displaced strand of a transcription-induced R-loop in vitro ...

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“…[3][4][5], which have been implicated in several transcription-dependent phenomena (for example, see refs. [6][7][8][9].…”

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confidence: 99%

Mechanisms and implications of transcription blockage by guanine-rich DNA sequences

Belotserkovskii

Liu

Tornaletti

et al. 2010

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

139

143

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Various DNA sequences that interfere with transcription due to their unusual structural properties have been implicated in the regulation of gene expression and with genomic instability. An important example is sequences containing G-rich homopurinehomopyrimidine stretches, for which unusual transcriptional behavior is implicated in regulation of immunogenesis and in other processes such as genomic translocations and telomere function. To elucidate the mechanism of the effect of these sequences on transcription we have studied T7 RNA polymerase transcription of G-rich sequences in vitro. We have shown that these sequences produce significant transcription blockage in an orientation-, lengthand supercoiling-dependent manner. Based upon the effects of various sequence modifications, solution conditions, and ribonucleotide substitutions, we conclude that transcription blockage is due to formation of unusually stable RNA/DNA hybrids, which could be further exacerbated by triplex formation. These structures are likely responsible for transcription-dependent replication blockage by G-rich sequences in vivo.R-loops | DNA supercoiling | Hoogsteen base pairing | inosine | 7-deazaquanosine S equence-specific modulation of transcription, including transcription blockage or impediment, plays an important role in DNA transactions, for example, transcription-related mutagenesis and recombination (reviewed in refs. 1 and 2) and could also be responsible for several severe genetic diseases (reviewed in refs. 3-5).Among the DNA sequences that could affect transcription are GC-rich homopurine-homopyrimidine (hPu/hPy) stretches. These sequences could form unusual DNA structures, including triplexes and G quadruplexes (reviewed in refs. 3-5), which have been implicated in several transcription-dependent phenomena (for example, see refs. 6-9).Another important property of these sequences is a dramatic asymmetry in the stabilities of RNA/DNA duplexes: The rPu/dPy duplex is significantly more stable, whereas the rPy/dPu duplex is less stable than a DNA/DNA duplex of the same sequence (10). The increased stability of rPu/dPy duplexes is likely responsible for stable R-loop formation by these sequences (11), although alternative DNA structures might also be involved (8,12,13).The simplest example of GC-rich hPu/hPy sequences, the G n ∕C n repeats, is abundant in various genomes, including transcribed domains (14, 15).The G 32 ∕C 32 stretch was previously shown to stall DNA replication in Escherichia coli plasmids in vivo (16). Remarkably, this effect was observed only when the sequence was transcribed, which led to a model stipulating that this sequence stalled an elongating RNA polymerase, and the stalled transcription complex, in turn, blocked the replication machinery (16).To elucidate the mechanism of transcription blockage by this sequence, we have studied its effect on T7 RNA polymerase (T7 RNAP) transcription in vitro, using various sequence modifications and solution conditions that allowed us to discriminate between possible D...

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AID binds to transcription-induced structures in c-MYC that map to regions associated with translocation and hypermutation

Cited by 129 publications

References 59 publications

Identification of two distinct MYC breakpoint clusters and their association with various IGH breakpoint regions in the t(8;14) translocations in sporadic Burkitt-lymphoma

Identification of two distinct MYC breakpoint clusters and their association with various IGH breakpoint regions in the t(8;14) translocations in sporadic Burkitt-lymphoma

Activation-induced cytidine deaminase action is strongly stimulated by mutations of the THO complex

Mechanisms and implications of transcription blockage by guanine-rich DNA sequences

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