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IgH class switching exploits a general property of two DNA breaks to be joined in cis over long chromosomal distances

Gostissa, M and Schwer, B and Chang, A and Dong, J and Meyers, RM and Marecki, GT and Choi, VW and Chiarle, R and Zarrin, AA and Alt, FW (2014) IgH class switching exploits a general property of two DNA breaks to be joined in cis over long chromosomal distances. Proceedings of the National Academy of Sciences of the United States of America. pp. 2644-2649.

Abstract

Antibody class switch recombination (CSR) in B lymphocytes joins two DNA double-strand breaks (DSBs) lying 100-200 kb apart within switch (S) regions in the immunoglobulin heavy-chain locus (IgH). CSR-activated B lymphocytes generate multiple S-region DSBs in the donor Su and in a downstream acceptor S region, with a DSB in Su being joined to a DSB in the acceptor S region at sufficient frequency to drive CSR in a large fraction of activated B cells. Such frequent joining of widely separated CSR DSBs could be promoted by IgH-specific or B-cell-specific processes or by general aspects of chromosome architecture and DSB repair. Previously, we found that B cellswith two yeast I-SceI endonuclease targets in place of S?1 undergo I-SceI-dependent class switching from IgM to IgG1 at 5-10% of normal levels. Now, we report that B cells in which S?1 is replaced with a 28 I-SceI target array, designed to increase I-SceI DSB frequency, undergo I-SceI-dependent class switching at almost normal levels. High-throughput genome-wide translocation sequencing revealed that I-SceI-generated DSBs introduced in cis at Su and S?1 sites are joined together in T cells at levels similar to those of B cells. Such high joining levels also occurred between I-SceI-generated DSBs within c-myc and I-SceI- or CRISPR/Cas9-generated DSBs 100 kb downstream within Pvt1 in B cells or fibroblasts, respectively.We suggest that CSR exploits a general propensity of intrachromosomal DSBs separated by several hundred kilobases to be frequently joined together and discuss the relevance of this finding for recurrent interstitial deletions in cancer

Item Type: Article
Additional Information: NIBR author: Choi, V institute: NIBR- address only contributor address: (Gostissa, Schwer, Chang, Dong, Meyers, Marecki, Choi, Chiarle, Zarrin, Alt) Howard Hughes Medical Institute, United States (Gostissa, Schwer, Chang, Dong, Meyers, Marecki, Choi, Chiarle, Zarrin, Alt) Program in Cellular and Molecular Medicine, Boston Children's Hospital, United States (Gostissa, Schwer, Chang, Dong, Meyers, Marecki, Choi, Chiarle, Zarrin, Alt) Department of Genetics, Harvard Medical School, Boston, MA 02115, United States (Choi) Novartis Institute for BioMedical Research, Cambridge, MA 02139, United States (Chiarle) Department of Pathology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, United States (Chiarle) Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126 Torino, Italy (Zarrin) Genentech, Inc., South San Francisco, CA 94080, United States
Date Deposited: 13 Oct 2015 13:12
Last Modified: 13 Oct 2015 13:12
URI: https://oak.novartis.com/id/eprint/22667

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