GONUTS has been updated to MW1.31 Most things seem to be working but be sure to report problems.

Have any questions? Please email us at ecoliwiki@gmail.com

PMID:18033247

From GONUTS
Jump to: navigation, search
Citation

Matthews, AG, Kuo, AJ, Ramón-Maiques, S, Han, S, Champagne, KS, Ivanov, D, Gallardo, M, Carney, D, Cheung, P, Ciccone, DN, Walter, KL, Utz, PJ, Shi, Y, Kutateladze, TG, Yang, W, Gozani, O and Oettinger, MA (2007) RAG2 PHD finger couples histone H3 lysine 4 trimethylation with V(D)J recombination. Nature 450:1106-10

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.

Links

PubMed PMC2988437 Online version:10.1038/nature06431

Keywords

Amino Acid Motifs; Animals; Binding Sites; DNA-Binding Proteins/chemistry; DNA-Binding Proteins/metabolism; Gene Rearrangement, B-Lymphocyte; Histones/chemistry; Histones/metabolism; Homeodomain Proteins/chemistry; Homeodomain Proteins/metabolism; Humans; Immunologic Deficiency Syndromes/genetics; Lysine/chemistry; Lysine/metabolism; Methylation; Mice; Models, Molecular; Protein Binding; Recombination, Genetic; Structure-Activity Relationship; Substrate Specificity; Tryptophan/genetics; Tryptophan/metabolism; VDJ Recombinases/chemistry; VDJ Recombinases/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:RAG2

located_in

GO:0005634: nucleus

ECO:0000305: curator inference used in manual assertion

GO:0035064

C

Seeded From UniProt

complete

MOUSE:RAG2

enables

GO:0035091: phosphatidylinositol binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:RAG2

enables

GO:0035064: methylated histone binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:RAG2

enables

GO:0003682: chromatin binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:RAG2

enables

GO:0008270: zinc ion binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:RAG2

part_of

GO:0005634: nucleus

ECO:0000305: curator inference used in manual assertion

GO:0035064

C

Seeded From UniProt

complete

MOUSE:RAG2

involved_in

GO:0033151: V(D)J recombination

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

See Help:References for how to manage references in GONUTS.