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Chu SH, Chabon JR, Matovina CN, et al. Loss of H3K36 Methyltransferase SETD2 Impairs V(D)J Recombination during Lymphoid Development. iScience. 2020;23(3):100941doi: 10.1016/j.isci.2020.100941.
Chu, S. H., Chabon, J. R., Matovina, C. N., Minehart, J. C., Chen, B. R., Zhang, J., Kumar, V., Xiong, Y., Callen, E., Hung, P. J., Feng, Z., Koche, R. P., Liu, X. S., Chaudhuri, J., Nussenzweig, A., Sleckman, B. P., & Armstrong, S. A. (2020). Loss of H3K36 Methyltransferase SETD2 Impairs V(D)J Recombination during Lymphoid Development. iScience, 23(3), 100941. https://doi.org/10.1016/j.isci.2020.100941
Chu, S Haihua, et al. "Loss of H3K36 Methyltransferase SETD2 Impairs V(D)J Recombination during Lymphoid Development." iScience vol. 23,3 (2020): 100941. doi: https://doi.org/10.1016/j.isci.2020.100941
Chu SH, Chabon JR, Matovina CN, Minehart JC, Chen BR, Zhang J, Kumar V, Xiong Y, Callen E, Hung PJ, Feng Z, Koche RP, Liu XS, Chaudhuri J, Nussenzweig A, Sleckman BP, Armstrong SA. Loss of H3K36 Methyltransferase SETD2 Impairs V(D)J Recombination during Lymphoid Development. iScience. 2020 Mar 27;23(3):100941. doi: 10.1016/j.isci.2020.100941. Epub 2020 Feb 27. PMID: 32169821; PMCID: PMC7066224.
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iScience. 2020 Mar 27;23(3):100941. doi: 10.1016/j.isci.2020.100941. Epub 2020 Feb 27.

Loss of H3K36 Methyltransferase SETD2 Impairs V(D)J Recombination during Lymphoid Development.

iScience

S Haihua Chu, Jonathan R Chabon, Chloe N Matovina, Janna C Minehart, Bo-Ruei Chen, Jian Zhang, Vipul Kumar, Yijun Xiong, Elsa Callen, Putzer J Hung, Zhaohui Feng, Richard P Koche, X Shirley Liu, Jayanta Chaudhuri, Andre Nussenzweig, Barry P Sleckman, Scott A Armstrong

Affiliations

  1. Department of Pediatric Oncology, Dana Farber Cancer Institute, and Division of Hematology/Oncology, Boston Children's Hospital, 450 Brookline Avenue, Boston, MA 02215-5450, USA.
  2. New York University School of Medicine, New York, NY, USA.
  3. Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA.
  4. Center for Computational Biology, Beijing Institute of Basic Medical Sciences, Beijing, China; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard T.H. Chan School of Public Health, Boston, MA, USA.
  5. Howard Hughes Medical Institute, Department of Pediatrics, Department of Genetics, Harvard Medical School, Boston, MA, USA; Harvard-MIT MD-PhD Program, Harvard Medical School, Boston, MA, USA.
  6. Laboratory of Genome Integrity, National Cancer Institute National Institutes of Health, Bethesda, MD, USA.
  7. Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
  8. Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  9. Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard T.H. Chan School of Public Health, Boston, MA, USA.
  10. Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, New York, NY, USA.
  11. Department of Pediatric Oncology, Dana Farber Cancer Institute, and Division of Hematology/Oncology, Boston Children's Hospital, 450 Brookline Avenue, Boston, MA 02215-5450, USA. Electronic address: [email protected].

PMID: 32169821 PMCID: PMC7066224 DOI: 10.1016/j.isci.2020.100941

Abstract

Repair of DNA double-stranded breaks (DSBs) during lymphocyte development is essential for V(D)J recombination and forms the basis of immunoglobulin variable region diversity. Understanding of this process in lymphogenesis has historically been centered on the study of RAG1/2 recombinases and a set of classical non-homologous end-joining factors. Much less has been reported regarding the role of chromatin modifications on this process. Here, we show a role for the non-redundant histone H3 lysine methyltransferase, Setd2, and its modification of lysine-36 trimethylation (H3K36me3), in the processing and joining of DNA ends during V(D)J recombination. Loss leads to mis-repair of Rag-induced DNA DSBs, especially when combined with loss of Atm kinase activity. Furthermore, loss reduces immune repertoire and a severe block in lymphogenesis as well as causes post-mitotic neuronal apoptosis. Together, these studies are suggestive of an important role of Setd2/H3K36me3 in these two mammalian developmental processes that are influenced by double-stranded break repair.

Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.

Keywords: Biological Sciences; Cell Biology; Immunology; Molecular Biology

Conflict of interest statement

Declaration of Interests S.A.A. has been a consultant and/or shareholder for Epizyme Inc, Imago Biosciences, Cyteir Therapeutics, C4 Therapeutics, Syros Pharmaceuticals, OxStem Oncology, Accent Therap

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