The mechanism of somatic hypermutation studied with transgenic and transfected target genes

Storb, Ursula; Peters, Andrew; Klotz, Emily; Rogerson, Brian J.; HackettJr, John

doi:10.1006/smim.1996.0017

Cited by 31 publications

(20 citation statements)

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“…Defining the mechanism of immunoglobulin mutation at the molecular level awaits the identification of at least some of the proteins involved. Possible mechanisms include error-prone DNA repair [28], the introduction of mutations in the lagging strand of replicating immunoglobulin genes that are then incorporated into the genome [29], or activity of a 'mutator' protein that could interact with the transcription initiation complex [5] or participate in RT-linked mutation [30]. Any of these models may implicate helicase activity to account for DNA accessibility required for base replacement.…”

Section: Discussionmentioning

confidence: 99%

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Somatic hypermutation of immunoglobulin genes is independent of the Bloom's syndrome DNA helicase

Sack

Liu

German

et al. 1998

Clinical and Experimental Immunology

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Immunoglobulin gene somatic mutation leads to antibody affinity maturation through the introduction of multiple point mutations in the antigen binding site. No genes have as yet been identified that participate in this process. Bloom's syndrome (BS) is a chromosomal breakage disorder with a mutator phenotype. Most affected individuals exhibit an immunodeficiency of undetermined aetiology. The gene for this disorder, BLM, has recently been identified as a DNA helicase. If this gene were to play a role in immunoglobulin mutation, then people with BS may lack normally mutated antibodies. Since germ-line, non-mutated immunoglobulin genes generally produce low affinity antibodies, impaired helicase activity might be manifested as the immunodeficiency found in BS. Therefore, we asked whether BLM is specifically involved in immunoglobulin hypermutation. Sequences of immunoglobulin variable (V) regions were analysed from small unsorted blood samples obtained from BS individuals and compared with germ-line sequences. BS V regions displayed the normal distribution of mutations, indicating that the defect in BS is not related to the mechanism of somatic mutation. These data strongly argue against BLM being involved in this process. The genetic approach to identifying the genes involved in immunoglobulin mutation will require further studies of DNA repair- and immunodeficient individuals.

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Section: Discussionmentioning

confidence: 99%

“…The molecular mechanism of hypermutation remains unclear. Possible mechanisms invoke DNA replication or repair, possibly linked to transcription [5]. None of the proteins involved in the mechanism of hypermutation has as yet been identified.…”

Section: Introductionmentioning

confidence: 99%

Somatic hypermutation of immunoglobulin genes is independent of the Bloom's syndrome DNA helicase

Sack

Liu

German

et al. 1998

Clinical and Experimental Immunology

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“…Although these characteristics were iuitially deduced from tbe sequences of rearranged productive endogenous antibody genes and cotild have reflected the powerful selection for B cells making higb affinity and non-self reactive antibodies, the analysis of non-productive genes and ofthe untranslated regions of productive genes have largely confirmed these fnidings (13,24,25). More recently, kappa L-chain transgenes have been introduced into the mouse genome (12,26,27). The analysis of these ectopically located transgenes, some of whicb are "passenger" genes (28) in that they are made in addition to tbe endogenous genes and therefore may not be subjected to as much selection, has so far confirmed the findings made with endogenous Ig alleles.…”

Section: Introductionmentioning

confidence: 90%

“…The analysis of these ectopically located transgenes, some of whicb are "passenger" genes (28) in that they are made in addition to tbe endogenous genes and therefore may not be subjected to as much selection, has so far confirmed the findings made with endogenous Ig alleles. In addition, these ectopically located Ig genes appear to contain sufficient information to regulate and target the mutational process (12,27), In some cases, non-Ig genes from other species have been introduced into transgenes in place of the V-region coding sequences aud they also undergo higb rates of mutation in vivo (29,30). In contrast, if either the intronic or 3' enhancers ofthe L-chain transgenes are removed, mutation does not occur at the normal rate despite adequate transcription of the transgene (31).…”

Section: Introductionmentioning

confidence: 99%

Immunoglobulin hypermutation in cultured cells

Green

Lin

Scharff³

1998

Immunological Reviews

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Studies of endogenous and engineered Ig genes in mice have begun to reveal some of the cis-acting regions that are involved in the somatic hypermutation of variable regions in vivo. These studies suggest that the initiation of transcription plays a role in this process. However, it will be difficult to identify and manipulate the individual genetic elements and the trans-acting proteins that regulate and target the mutational events using solely in vivo assays. These studies would be greatly facilitated if constructs containing the genetic elements that are essential for V-region mutation could be transfected into cultured cells and undergo high rates of V-region mutation in vitro, and if permissive and non-permissive cell lines could be identified. Such in vitro systems would also allow a detailed molecular and biochemical analysis of this process. Here, we discuss some of the in vitro systems that have been developed and use data from our own studies in cultured cells to illustrate the potential benefits of studying V-region hypermutation in model in vitro systems.

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“…A large body of evidence from both prokaryotes and eukaryotes indicates that transcription plays a central role in the induction of spontaneous genomic instability [7, 34, 82, 83]. This phenomenon, termed transcription-associated recombination (TAR), is involved in developmentally-regulated processes such as class switch recombination of immunoglobulin (Ig) genes [5, 84, 85]. Since stalled replication forks trigger HR [1, 3, 4], a likely possibility is that transcription promotes genomic instability by blocking replication forks [7, 34].…”

Section: Functional Links Between Transcription Replication and Recomentioning

confidence: 99%

Interference Between DNA Replication and Transcription as a Cause of Genomic Instability

Lin¹,

Pasero²

2012

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Replication and transcription are key aspects of DNA metabolism that take place on the same template and potentially interfere with each other. Conflicts between these two activities include head-on or co-directional collisions between DNA and RNA polymerases, which can lead to the formation of DNA breaks and chromosome rearrangements. To avoid these deleterious consequences and prevent genomic instability, cells have evolved multiple mechanisms preventing replication forks from colliding with the transcription machinery. Yet, recent reports indicate that interference between replication and transcription is not limited to physical interactions between polymerases and that other cotranscriptional processes can interfere with DNA replication. These include DNA-RNA hybrids that assemble behind elongating RNA polymerases, impede fork progression and promote homologous recombination. Here, we discuss recent evidence indicating that R-loops represent a major source of genomic instability in all organisms, from bacteria to human, and are potentially implicated in cancer development.

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The mechanism of somatic hypermutation studied with transgenic and transfected target genes

Cited by 31 publications

References 0 publications

Somatic hypermutation of immunoglobulin genes is independent of the Bloom's syndrome DNA helicase

Somatic hypermutation of immunoglobulin genes is independent of the Bloom's syndrome DNA helicase

Immunoglobulin hypermutation in cultured cells

Interference Between DNA Replication and Transcription as a Cause of Genomic Instability

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