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Somatic hypermutation in the absence of DNA-dependent protein kinase catalytic subunit (DNA-PK(cs)) or recombination-activating gene (RAG)1 activity

Bemark, Mats LU orcid ; Sale, Julian E. ; Kim, Hye Jung ; Berek, Claudia ; Cosgrove, Ruth A. and Neuberger, Michael S. (2000) In Journal of Experimental Medicine 192(10). p.1509-1514
Abstract

Somatic hypermutation and isotype switch recombination occur in germinal center B cells, are linked to transcription, and are similarly affected by deficiency in MutS homologue (MSH)2. Class-switch recombination is abrogated by disruption of genes encoding components of the catalytic subunit of DNA-dependent protein kinase (DNA-PK(cs))/Ku complex and likely involves nonhomologous end joining (NHEJ). That somatic hypermutation might also be associated with end joining is suggested by its association with the creation of deletions, duplications, and sites accessible to terminal transferase. However, a requirement for NHEJ in the mutation process has not been demonstrated. Here we show that somatic mutation in mice deficient in NHEJ can be... (More)

Somatic hypermutation and isotype switch recombination occur in germinal center B cells, are linked to transcription, and are similarly affected by deficiency in MutS homologue (MSH)2. Class-switch recombination is abrogated by disruption of genes encoding components of the catalytic subunit of DNA-dependent protein kinase (DNA-PK(cs))/Ku complex and likely involves nonhomologous end joining (NHEJ). That somatic hypermutation might also be associated with end joining is suggested by its association with the creation of deletions, duplications, and sites accessible to terminal transferase. However, a requirement for NHEJ in the mutation process has not been demonstrated. Here we show that somatic mutation in mice deficient in NHEJ can be tested by introduction of rearranged immunoglobulin and T cell receptor transgenes: the transgene combination not only permits reconstitution of peripheral lymphoid compartments but also allows formation of germinal centers, despite the wholly monoclonal nature of the lymphocyte antigen receptors in these animals. Using this strategy, we confirm that somatic hypermutation like class-switching can occur in the absence of recombination-activating gene (RAG)1 but show that the two processes differ in that hypermutation can proceed essentially unaffected by deficiency in DNA-PK(cs) activity.

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author
; ; ; ; and
publishing date
type
Contribution to journal
publication status
published
subject
keywords
B lymphocyte, End-joining, Immunoglobulin gene, Mutation, Switch recombination
in
Journal of Experimental Medicine
volume
192
issue
10
pages
1509 - 1514
publisher
Rockefeller University Press
external identifiers
  • pmid:11085752
  • scopus:0034694086
ISSN
0022-1007
DOI
10.1084/jem.192.10.1509
language
English
LU publication?
no
id
bb993f63-1f72-4f2c-8f30-a47c911e98b7
date added to LUP
2023-12-06 16:47:46
date last changed
2024-02-19 09:27:41
@article{bb993f63-1f72-4f2c-8f30-a47c911e98b7,
  abstract     = {{<p>Somatic hypermutation and isotype switch recombination occur in germinal center B cells, are linked to transcription, and are similarly affected by deficiency in MutS homologue (MSH)2. Class-switch recombination is abrogated by disruption of genes encoding components of the catalytic subunit of DNA-dependent protein kinase (DNA-PK(cs))/Ku complex and likely involves nonhomologous end joining (NHEJ). That somatic hypermutation might also be associated with end joining is suggested by its association with the creation of deletions, duplications, and sites accessible to terminal transferase. However, a requirement for NHEJ in the mutation process has not been demonstrated. Here we show that somatic mutation in mice deficient in NHEJ can be tested by introduction of rearranged immunoglobulin and T cell receptor transgenes: the transgene combination not only permits reconstitution of peripheral lymphoid compartments but also allows formation of germinal centers, despite the wholly monoclonal nature of the lymphocyte antigen receptors in these animals. Using this strategy, we confirm that somatic hypermutation like class-switching can occur in the absence of recombination-activating gene (RAG)1 but show that the two processes differ in that hypermutation can proceed essentially unaffected by deficiency in DNA-PK(cs) activity.</p>}},
  author       = {{Bemark, Mats and Sale, Julian E. and Kim, Hye Jung and Berek, Claudia and Cosgrove, Ruth A. and Neuberger, Michael S.}},
  issn         = {{0022-1007}},
  keywords     = {{B lymphocyte; End-joining; Immunoglobulin gene; Mutation; Switch recombination}},
  language     = {{eng}},
  month        = {{11}},
  number       = {{10}},
  pages        = {{1509--1514}},
  publisher    = {{Rockefeller University Press}},
  series       = {{Journal of Experimental Medicine}},
  title        = {{Somatic hypermutation in the absence of DNA-dependent protein kinase catalytic subunit (DNA-PK(cs)) or recombination-activating gene (RAG)1 activity}},
  url          = {{http://dx.doi.org/10.1084/jem.192.10.1509}},
  doi          = {{10.1084/jem.192.10.1509}},
  volume       = {{192}},
  year         = {{2000}},
}