RAG2 PHD finger couples histone H3 lysine 4 trimethylation with V(D)J recombination

Adam G.W. Matthews, Alex J. Kuo, Santiago Ramón-Maiques, Sunmi Han, Karen S. Champagne, Dmitri Ivanov, Mercedes Gallardo, Dylan Carney, Peggie Cheung, David N. Ciccone, Kay L. Walter, Paul J. Utz, Yang Shi, Tatiana G. Kutateladze, Wei Yang, Or Gozani, Marjorie A. Oettinger

Research output: Contribution to journalArticlepeer-review

338 Scopus citations

Abstract

Nuclear processes such as transcription, DNA replication and recombination are dynamically regulated by chromatin structure. Eukaryotic transcription is known to be regulated by chromatin-associated proteins containing conserved protein domains that specifically recognize distinct covalent post-translational modifications on histones. However, it has been unclear whether similar mechanisms are involved in mammalian DNA recombination. Here we show that RAG2 - an essential component of the RAG1/2 V(D)J recombinase, which mediates antigen-receptor gene assembly - contains a plant homeodomain (PHD) finger that specifically recognizes histone H3 trimethylated at lysine 4 (H3K4me3). The high-resolution crystal structure of the mouse RAG2 PHD finger bound to H3K4me3 reveals the molecular basis of H3K4me3-recognition by RAG2. Mutations that abrogate RAG2's recognition of H3K4me3 severely impair V(D)J recombination in vivo. Reducing the level of H3K4me3 similarly leads to a decrease in V(D)J recombination in vivo. Notably, a conserved tryptophan residue (W453) that constitutes a key structural component of the K4me3-binding surface and is essential for RAG2's recognition of H3K4me3 is mutated in patients with immunodeficiency syndromes. Together, our results identify a new function for histone methylation in mammalian DNA recombination. Furthermore, our results provide the first evidence indicating that disrupting the read-out of histone modifications can cause an inherited human disease.

Original languageEnglish (US)
Pages (from-to)1106-1110
Number of pages5
JournalNature
Volume450
Issue number7172
DOIs
StatePublished - Dec 13 2007
Externally publishedYes

ASJC Scopus subject areas

  • General

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