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Davari, K.* ; Frankenberger, S. ; Schmidt, A.* ; Tomi, N.S.* ; Jungnickel, B.*

Checkpoint kinase 2 is required for efficient immunoglobulin diversification.

Cell Cycle 13, 3659-3669 (2014)
Verlagsversion DOI PMC
Closed
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
Maintenance of genome integrity relies on multiple DNA repair pathways as well as on checkpoint regulation. Activation of the checkpoint kinases Chk1 and Chk2 by DNA damage triggers cell cycle arrest and improved DNA repair, or apoptosis in case of excessive damage. Chk1 and Chk2 have been reported to act in a complementary or redundant fashion, depending on the physiological context. During secondary immunoglobulin (Ig) diversification in B lymphocytes, DNA damage is abundantly introduced by activation-induced cytidine deaminase (AID) and processed to mutations in a locus-specific manner by several error-prone DNA repair pathways. We have previously shown that Chk1 negatively regulates Ig somatic hypermutation by promoting error-free homologous recombination and Ig gene conversion. We now report that Chk2 shows opposite effects to Chk1 in the regulation of these processes. Chk2 inactivation in B cells leads to decreased Ig hypermutation and Ig class switching, and increased Ig gene conversion activity. This is linked to defects in non-homologous end joining and increased Chk1 activation upon interference with Chk2 function. Intriguingly, in the context of physiological introduction of substantial DNA damage into the genome during Ig diversification, the 2 checkpoint kinases thus function in an opposing manner, rather than redundantly or cooperatively.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Aid, Activation-induced Cytidine Deaminase ; Ape1, Apurinic Endonuclease 1 ; Atm, Ataxia Telangiectasia Mutated ; Atr, Ataxia Telangiectasia And Rad3 Related ; Chk, Checkpoint Kinase ; Dna Repair ; Hr, Homologous Recombination ; Ig, Immunoglobulin ; Mmr Mismatch Repair ; Mms, Methyl Methansulfonate ; Nhej, Non-homologous End Joining ; Ung, Uracil N-glycosilase ; Checkpoint Signaling ; Germinal Center ; Immunoglobulin Diversification; Induced Cytidine Deaminase; Class-switch Recombination; Double-strand Breaks; Center B-cells; Activation-induced Deaminase; Uracil-dna Glycosylase; Somatic Hypermutation; Gene Conversion; Homologous Recombination; Targeted Disruption
Sprache englisch
Veröffentlichungsjahr 2014
HGF-Berichtsjahr 2014
ISSN (print) / ISBN 1538-4101
e-ISSN 1551-4005
Zeitschrift Cell Cycle
Quellenangaben Band: 13, Heft: 23, Seiten: 3659-3669 Artikelnummer: , Supplement: ,
Verlag Landes Bioscience
Verlagsort Austin
Begutachtungsstatus Peer reviewed
Institut(e) Research Unit Gene Vector (AGV)
Institute of Clinical Molecular Biology and Tumor Genetics (K.MOLBI)
POF Topic(s) 30203 - Molecular Targets and Therapies
30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
Forschungsfeld(er) Immune Response and Infection
PSP-Element(e) G-501500-003
G-501400-001
PubMed ID 25483076
DOI 10.4161/15384101.2014.964112
WOS ID WOS:000348329200010
Scopus ID 84920628994
Erfassungsdatum 2014-12-31
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