An autoregulatory mechanism imposes allosteric control on the V(D)J recombinase by histone H3 methylation

Chao Lu, Alyssa Ward, John Bettridge, Yun Liu, Stephen Desiderio

Research output: Contribution to journalArticle

Abstract

V(D)J recombination is initiated by a specialized transposase consisting of the subunits RAG-1 and RAG-2. The susceptibility of gene segments to DNA cleavage by the V(D)J recombinase is correlated with epigenetic modifications characteristic of active chromatin, including trimethylation of histone H3 onlysine 4 (H3K4me3). Engagement of H3K4me3 by aplant homeodomain (PHD) in RAG-2 promotes recombination invivo and stimulates DNA cleavage by RAG invitro. We now show that H3K4me3 acts allosterically at the PHD finger to relieve autoinhibition imposed by a separate domain within RAG-2. Disruption of this autoinhibitory domain was associated with constitutive increases in recombination frequency, DNA cleavage activity, substrate binding affinity, and catalytic rate, thus mimicking the stimulatory effects of H3K4me3. Our observations support a model in which allosteric control of RAG is enforced by an autoinhibitory domain whose action is relieved by engagement of active chromatin.

Original languageEnglish (US)
Pages (from-to)29-38
Number of pages10
JournalCell Reports
Volume10
Issue number1
DOIs
StatePublished - Jan 6 2015

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VDJ Recombinases
Histones
Methylation
Genetic Recombination
Chromatin
Blood Flow Velocity
V(D)J Recombination
Transposases
Epigenomics
Genes
Aortic Arch Syndromes
Cyclic AMP Receptor Protein
Anthralin
Substrates

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

An autoregulatory mechanism imposes allosteric control on the V(D)J recombinase by histone H3 methylation. / Lu, Chao; Ward, Alyssa; Bettridge, John; Liu, Yun; Desiderio, Stephen.

In: Cell Reports, Vol. 10, No. 1, 06.01.2015, p. 29-38.

Research output: Contribution to journalArticle

Lu, Chao; Ward, Alyssa; Bettridge, John; Liu, Yun; Desiderio, Stephen / An autoregulatory mechanism imposes allosteric control on the V(D)J recombinase by histone H3 methylation.

In: Cell Reports, Vol. 10, No. 1, 06.01.2015, p. 29-38.

Research output: Contribution to journalArticle

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