title: Checkpoint kinase 2 is required for efficient immunoglobulin diversification.
abstract: 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.
authors.affiliation: a Department of Cell Biology; Institute of Biochemistry and Biophysics; Center for Molecular Biomedicine ; Friedrich-Schiller University Jena ; Jena , Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Davari
authors.forename: Samantha
authors.initials: S
authors.lastname: Frankenberger
authors.forename: Angelika
authors.initials: A
authors.lastname: Schmidt
authors.forename: Nils-Sebastian
authors.initials: NS
authors.lastname: Tomi
authors.forename: Berit
authors.initials: B
authors.lastname: Jungnickel
mesh_terms: D001402:B-Lymphocytes / Q000201:enzymology; D002470:Cell Survival / Q000502:physiology; D000071877:Checkpoint Kinase 1; D064447:Checkpoint Kinase 2 / Q000172:deficiency* / Q000235:genetics; D055786:Gene Knockout Techniques / Q000379:methods; D006801:Humans; D007136:Immunoglobulins / Q000502:physiology*; D011494:Protein Kinases / Q000172:deficiency* / Q000235:genetics
chemical_list: D007136:Immunoglobulins; D011494:Protein Kinases; D064447:Checkpoint Kinase 2; C000605867:CHEK1 protein, human; C578634:CHEK2 protein, human; D000071877:Checkpoint Kinase 1
keywords: 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