CNOT3 contributes to early B cell development by controlling Igh rearrangement and p53 mRNA stability

Takeshi Inoue, Masahiro Morita, Atsushi Hijikata, Fukuda-Yuzawa Yoko Fukuda-Yuzawa, Shungo Adachi, Kyoichi Isono, Tomokatsu Ikawa, Hiroshi Kawamoto, Haruhiko Koseki, Tohru Natsume, Taro Fukao, Osamu Ohara, Tadashi Yamamoto, Tomohiro Kurosaki

Research output: Contribution to journalArticlepeer-review

31 Citations (Scopus)

Abstract

The CCR4-NOT deadenylase complex plays crucial roles in mRNA decay and translational repression induced by poly(A) tail shortening. Although the in vitro activities of each component of this complex have been well characterized, its in vivo role in immune cells remains unclear. Here we show that mice lacking the CNOT3 subunit of this complex, specifically in B cells, have a developmental block at the pro- to pre-B cell transition. CNOT3 regulated generation of germline transcripts in the VH region of the immunoglobulin heavy chain (Igh) locus, compaction of the locus, and subsequent Igh gene rearrangement and destabilized tumor suppressor p53 mRNA. The developmental defect in the absence of CNOT3 could be partially rescued by ablation of p53 or introduction of a prerearranged Igh transgene. Thus, our data suggest that the CCR4-NOT complex regulates B cell differentiation by controlling Igh rearrangement and destabilizing p53 mRNA.

Original languageEnglish
Pages (from-to)1465-1479
Number of pages15
JournalJournal of Experimental Medicine
Volume212
Issue number9
DOIs
Publication statusPublished - 24-08-2015
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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