Polζ ablation in B cells impairs the germinal center reaction, class switch recombination, DNA break repair, and genome stability

Dominik Schenten, Sven Kracker, Gloria Esposito, Sonia Franco, Ulf Klein, Michael Murphy, Frederick W. Alt, Klaus Rajewsky

Research output: Contribution to journalArticle

49 Citations (Scopus)

Abstract

Polζ is an error-prone DNA polymerase that is critical for embryonic development and maintenance of genome stability. To analyze its suggested role in somatic hypermutation (SHM) and possible contribution to DNA double-strand break (DSB) repair in class switch recombination (CSR), we ablated Rev3, the catalytic subunit of Polζ, selectively in mature B cells in vivo. The frequency of somatic mutation was reduced in the mutant cells but the pattern of SHM was unaffected. Rev3-deficient B cells also exhibited pronounced chromosomal instability and impaired proliferation capacity. Although the data thus argue against a direct role of Polζ in SHM, Polζ deficiency directly interfered with CSR in that activated Rev3-deficient B cells exhibited a reduced efficiency of CSR and an increased frequency of DNA breaks in the immunoglobulin H locus. Based on our results, we suggest a nonredun- dant role of Polζ in DNA DSB repair through nonhomologous end joining.

Original languageEnglish (US)
Pages (from-to)477-490
Number of pages14
JournalJournal of Experimental Medicine
Volume206
Issue number2
DOIs
StatePublished - Feb 16 2009
Externally publishedYes

Fingerprint

DNA Breaks
Germinal Center
Genomic Instability
DNA Repair
Genetic Recombination
B-Lymphocytes
Double-Stranded DNA Breaks
Chromosomal Instability
Mutation Rate
DNA-Directed DNA Polymerase
Embryonic Development
Immunoglobulins
Catalytic Domain
Maintenance

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy
  • Medicine(all)

Cite this

Polζ ablation in B cells impairs the germinal center reaction, class switch recombination, DNA break repair, and genome stability. / Schenten, Dominik; Kracker, Sven; Esposito, Gloria; Franco, Sonia; Klein, Ulf; Murphy, Michael; Alt, Frederick W.; Rajewsky, Klaus.

In: Journal of Experimental Medicine, Vol. 206, No. 2, 16.02.2009, p. 477-490.

Research output: Contribution to journalArticle

Schenten, Dominik ; Kracker, Sven ; Esposito, Gloria ; Franco, Sonia ; Klein, Ulf ; Murphy, Michael ; Alt, Frederick W. ; Rajewsky, Klaus. / Polζ ablation in B cells impairs the germinal center reaction, class switch recombination, DNA break repair, and genome stability. In: Journal of Experimental Medicine. 2009 ; Vol. 206, No. 2. pp. 477-490.
@article{b26915fe92f9416c9a8b77a5b19f1223,
title = "Polζ ablation in B cells impairs the germinal center reaction, class switch recombination, DNA break repair, and genome stability",
abstract = "Polζ is an error-prone DNA polymerase that is critical for embryonic development and maintenance of genome stability. To analyze its suggested role in somatic hypermutation (SHM) and possible contribution to DNA double-strand break (DSB) repair in class switch recombination (CSR), we ablated Rev3, the catalytic subunit of Polζ, selectively in mature B cells in vivo. The frequency of somatic mutation was reduced in the mutant cells but the pattern of SHM was unaffected. Rev3-deficient B cells also exhibited pronounced chromosomal instability and impaired proliferation capacity. Although the data thus argue against a direct role of Polζ in SHM, Polζ deficiency directly interfered with CSR in that activated Rev3-deficient B cells exhibited a reduced efficiency of CSR and an increased frequency of DNA breaks in the immunoglobulin H locus. Based on our results, we suggest a nonredun- dant role of Polζ in DNA DSB repair through nonhomologous end joining.",
author = "Dominik Schenten and Sven Kracker and Gloria Esposito and Sonia Franco and Ulf Klein and Michael Murphy and Alt, {Frederick W.} and Klaus Rajewsky",
year = "2009",
month = "2",
day = "16",
doi = "10.1084/jem.20080669",
language = "English (US)",
volume = "206",
pages = "477--490",
journal = "Journal of Experimental Medicine",
issn = "0022-1007",
publisher = "Rockefeller University Press",
number = "2",

}

TY - JOUR

T1 - Polζ ablation in B cells impairs the germinal center reaction, class switch recombination, DNA break repair, and genome stability

AU - Schenten, Dominik

AU - Kracker, Sven

AU - Esposito, Gloria

AU - Franco, Sonia

AU - Klein, Ulf

AU - Murphy, Michael

AU - Alt, Frederick W.

AU - Rajewsky, Klaus

PY - 2009/2/16

Y1 - 2009/2/16

N2 - Polζ is an error-prone DNA polymerase that is critical for embryonic development and maintenance of genome stability. To analyze its suggested role in somatic hypermutation (SHM) and possible contribution to DNA double-strand break (DSB) repair in class switch recombination (CSR), we ablated Rev3, the catalytic subunit of Polζ, selectively in mature B cells in vivo. The frequency of somatic mutation was reduced in the mutant cells but the pattern of SHM was unaffected. Rev3-deficient B cells also exhibited pronounced chromosomal instability and impaired proliferation capacity. Although the data thus argue against a direct role of Polζ in SHM, Polζ deficiency directly interfered with CSR in that activated Rev3-deficient B cells exhibited a reduced efficiency of CSR and an increased frequency of DNA breaks in the immunoglobulin H locus. Based on our results, we suggest a nonredun- dant role of Polζ in DNA DSB repair through nonhomologous end joining.

AB - Polζ is an error-prone DNA polymerase that is critical for embryonic development and maintenance of genome stability. To analyze its suggested role in somatic hypermutation (SHM) and possible contribution to DNA double-strand break (DSB) repair in class switch recombination (CSR), we ablated Rev3, the catalytic subunit of Polζ, selectively in mature B cells in vivo. The frequency of somatic mutation was reduced in the mutant cells but the pattern of SHM was unaffected. Rev3-deficient B cells also exhibited pronounced chromosomal instability and impaired proliferation capacity. Although the data thus argue against a direct role of Polζ in SHM, Polζ deficiency directly interfered with CSR in that activated Rev3-deficient B cells exhibited a reduced efficiency of CSR and an increased frequency of DNA breaks in the immunoglobulin H locus. Based on our results, we suggest a nonredun- dant role of Polζ in DNA DSB repair through nonhomologous end joining.

UR - http://www.scopus.com/inward/record.url?scp=63049129975&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=63049129975&partnerID=8YFLogxK

U2 - 10.1084/jem.20080669

DO - 10.1084/jem.20080669

M3 - Article

C2 - 19204108

AN - SCOPUS:63049129975

VL - 206

SP - 477

EP - 490

JO - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

SN - 0022-1007

IS - 2

ER -