The origin of a developmentally regulated<i>Igh</i>replicon is located near the border of regulatory domains for<i>Igh</i>replication and expression

Zhou, Jie; Ashouian, Nasrin; Délépine, Marc; Matsuda, Fumihiko; Chevillard, Christophe; Riblet, Roy; Schildkraut, Carl L.; Birshtein, Barbara K.

doi:10.1073/pnas.212392399

Cited by 47 publications

(38 citation statements)

References 62 publications

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“…48 This could come about by the asynchronous replication of the V-region in which Okazaki fragments preferentially occur on the top strand because of an origin of replication downstream of the V region. 50 Because MMR preferentially excises the lagging strand, 51 and if AID mutates the bottom strand, this would create the aforementioned scenario, leading to the concerted activity of MMR and UNG in stimulating mutations at A:T base pairs. We observed that the background level of mutation increased by 5-fold from the follicular B-cell stage to the GC B-cell stage.…”

Section: Discussionmentioning

confidence: 99%

The mismatch repair pathway functions normally at a non-AID target in germinal center B cells

Green

Belcheva

Nepal

et al. 2011

Blood

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IntroductionMismatch repair (MMR) is an evolutionary conserved DNA repair pathway that is required to repair mutations that arise through DNA replication or other processes. 1,2 MutS homologue 2 (Msh2) dimerizes with either Msh6 or Msh3 to recognize single base-pair mismatches or mismatches caused by insertion/deletions, respectively. 2 After binding to the mismatch, Msh2 hydrolyzes ATP, which induces a change in the heterodimer that allows for the recruitment of downstream repair factors such as MutL homologue 1, postmeiotic segregation 2, and exonuclease 1 (Exo1). 3,4 Because of Msh2's essential role in repairing DNA mutations, Msh2 Ϫ/Ϫ mice have 5-fold, 11-fold, and 15-fold greater mutation frequencies in the brain, small intestine, and thymus, respectively, 5 and are predisposed to cancer. [6][7][8] During an immune response, Ig genes undergo somatic hypermutation (SHM) to produce high-affinity antibodies. SHM is initiated by activation-induced cytidine deaminase (AID), 9 which deaminates cytidine molecules within the V region to produce dU:dG mispairs. [10][11][12] The dU:dG mismatch is recognized by the Msh2/Msh6 heterodimer, but instead of repairing this mutation, MMR produces mutations. [13][14][15][16][17][18] Mice deficient in Msh2, Msh6, postmeiotic segregation 2, MutL homologue 1, or Exo1 have an approximately 2-fold decrease in overall mutation frequency at the V region. 13,14,[16][17][18] In particular, there is an approximately10-fold decrease in mutations at A:T base pairs at the V region in MSH2-deficient mice, whereas the mutation frequency at G:C base pairs is unaltered. [15][16][17][18][19] These results indicate that the MMR pathway is required to produce mutations at A:T base pairs in the V region. MMR proteins have also been implicated in mutagenic processes that cause disease, including trinucleotide-repeat diseases. 20 Two sets of recent results suggest the possibility that the MMR system is generally defective in germinal center (GC) B cells.Ouchida et al 21 reported that GC B cells have a generally greater mutation rate than other cells, as measured by the frequency of mutations on a lacZ transgene. Liu et al 22 found that in Msh2 mutant mice, the mutation frequency of AID-sensitive genes was either lower or only slightly greater than in wild-type (WT) cells; they argued that the Msh2-dependent pathway was not functioning normally in GC cells. Together, these results would fit a simple unified model in which the expression of a GC/B cell-specific factor commandeers MMR and transforms this DNA repair pathway into a mutagenic pathway.An alternative explanation is that the MMR pathway is only mutagenic at sites mutated by AID, which would argue against a factor that disrupts global MMR function in GC B cells. To explore this issue, we examined the impact of Msh2-deficiency at a lacI transgene that is not mutated by AID in GC B cells. Our results indicate that Msh2 efficiently repairs lacI mutations in all cell populations examined, including GC B cells. Thus, MMR functions normally in GC ...

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Section: Discussionmentioning

confidence: 99%

The mismatch repair pathway functions normally at a non-AID target in germinal center B cells

Green

Belcheva

Nepal

et al. 2011

Blood

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“…In human mtDNA, replication appears to be more frequent in the O H proximal part of the initiation zone. There are a number of reports of initiation zones, including several in mammalian nuclear DNA such as, for example, dihydrofolate reductase (27), ␤-globin (28), and immunoglobulin H loci (29).…”

Section: Replication Origins Of Rat Mtdna Map To a Broad Region Downsmentioning

confidence: 99%

Mammalian Mitochondrial DNA Replicates Bidirectionally from an Initiation Zone

Bowmaker

Yang

Yasukawa

et al. 2003

Journal of Biological Chemistry

183

171

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Previous data from our laboratory suggested that replication of mammalian mitochondrial DNA initiates exclusively at or near to the formerly designated origin of heavy strand replication, O H , and proceeds unidirectionally from that locus. New results obtained using twodimensional agarose gel electrophoresis of replication intermediates demonstrate that replication of mitochondrial DNA initiates from multiple origins across a broad zone. After fork arrest near O H , replication is restricted to one direction only. The initiation zone of bidirectional replication includes the genes for cytochrome b and NADH dehydrogenase subunits 5 and 6.

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“…This occurs during differentiation of Xenopus (Hyrien et al 1995) and Sciara (Lunyak et al 2002) embryos, at the Chinese hamster Dhfr locus (Saha et al 2004), and at the murine HoxB locus (Gregoire et al 2006). Conversely, at the human IGH locus (Zhou et al 2002) replication initiates in an expanded region after the onset of transcription; and on human (Gray et al 2007) and murine (Rowntree and Lee 2006) X chromosomes, replication initiates from distinct origins regardless of transcriptional status. Finally, at the human MYC locus, transcription factor binding seems to activate initiation of DNA replication, whereas high transcription rates suppress it (Ghosh et al 2004).…”

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confidence: 99%

Genome-wide depletion of replication initiation events in highly transcribed regions

et al. 2011

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This report investigates the mechanisms by which mammalian cells coordinate DNA replication with transcription and chromatin assembly. In yeast, DNA replication initiates within nucleosome-free regions, but studies in mammalian cells have not revealed a similar relationship. Here, we have used genome-wide massively parallel sequencing to map replication initiation events, thereby creating a database of all replication initiation sites within nonrepetitive DNA in two human cell lines. Mining this database revealed that genomic regions transcribed at moderate levels were generally associated with high replication initiation frequency. In genomic regions with high rates of transcription, very few replication initiation events were detected. High-resolution mapping of replication initiation sites showed that replication initiation events were absent from transcription start sites but were highly enriched in adjacent, downstream sequences. Methylation of CpG sequences strongly affected the location of replication initiation events, whereas histone modifications had minimal effects. These observations suggest that high levels of transcription interfere with formation of pre-replication protein complexes. Data presented here identify replication initiation sites throughout the genome, providing a foundation for further analyses of DNA-replication dynamics and cell-cycle progression.

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The origin of a developmentally regulatedIghreplicon is located near the border of regulatory domains forIghreplication and expression

Cited by 47 publications

References 62 publications

The mismatch repair pathway functions normally at a non-AID target in germinal center B cells

The mismatch repair pathway functions normally at a non-AID target in germinal center B cells

Mammalian Mitochondrial DNA Replicates Bidirectionally from an Initiation Zone

Genome-wide depletion of replication initiation events in highly transcribed regions

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