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Regulation of the DNA Repair Complex during Somatic Hypermutation and Class-Switch Recombination
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
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2018 (English)In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 200, no 12, p. 4146-4156Article in journal (Refereed) Published
Abstract [en]

B lymphocytes optimize Ab responses by somatic hypermutation (SH), which introduces pointmutations in the variable regions of the Ab genes and by class-switch recombination (CSR), which changes the expressed C region exon of the IgH. These Ab diversification processes are initiated by the deaminating enzyme activation-induced cytidine deaminase followed by many DNA repair enzymes, ultimately leading to deletions and a high mutation rate in the Ab genes, whereas DNA lesions made by activation-induced cytidine deaminase are repaired with low error rate on most other genes. This indicates an advanced regulation of DNA repair. In this study, we show that initiation of Ab diversification in B lymphocytes of mouse spleen leads to formation of a complex between many proteins in DNA repair. We show also thatBCR activation, which signals the end of successful SH, reduces interactions between some proteins in the complex and increases other interactions in the complex with varying kinetics. Furthermore, we show increased localization of SH-and CSR-coupled proteins on switch regions of the Igh locus upon initiation of SH/CSR and differential changes in the localization upon BCR signaling, which terminates SH. These findings provide early evidence for a DNA repair complex or complexes that may be of functional significance for carrying out essential roles in SH and/or CSR in B cells.

Place, publisher, year, edition, pages
American Association of Immunologists , 2018. Vol. 200, no 12, p. 4146-4156
National Category
Immunology in the medical area
Identifiers
URN: urn:nbn:se:umu:diva-151570DOI: 10.4049/jimmunol.1701586ISI: 000442386300029PubMedID: 29728513OAI: oai:DiVA.org:umu-151570DiVA, id: diva2:1246856
Funder
Swedish Cancer SocietySwedish Research CouncilAvailable from: 2018-09-10 Created: 2018-09-10 Last updated: 2018-09-10Bibliographically approved

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Kumar, AnjaniPriya, AnshuAhmed, TanzeelGrundström, ChristineNegi, NeemaGrundström, Thomas

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