title: The RING domain of RAG1 ubiquitylates histone H3: a novel activity in chromatin-mediated regulation of V(D)J joining.
abstract: The RAG1 and RAG2 proteins are the only lymphoid-specific factors required to perform the first step of V(D)J recombination, DNA cleavage. While the catalytic domain of RAG1, the core region, has been well characterized, the role of the noncore region in modulating chromosomal V(D)J recombination efficiency remains ill defined. Recent studies have highlighted the role of chromatin structure in regulation of V(D)J recombination. Here we show that RAG1 itself, through a RING domain within its N-terminal noncore region, preferentially interacts directly with and promotes monoubiquitylation of histone H3. Mutations affecting the RAG1 RING domain reduce histone H3 monoubiquitylation activity, decrease V(D)J recombination activity in vivo, reduce formation of both signal-joint and coding-joint products on episomal substrates, and decrease efficiency of V(D)J recombination at the endogenous IgH locus in lymphoid cells. The results reveal that RAG1-mediated histone monoubiquitylation activity plays a role in regulating the joining phase of chromosomal V(D)J recombination.
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan 20141, Italy.
authors.forename: Ursula
authors.initials: U
authors.lastname: Grazini
authors.forename: Federica
authors.initials: F
authors.lastname: Zanardi
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Citterio
authors.forename: Stefano
authors.initials: S
authors.lastname: Casola
authors.forename: Colin R
authors.initials: CR
authors.lastname: Goding
authors.forename: Fraser
authors.initials: F
authors.lastname: McBlane
mesh_terms: D001665:Binding Sites; D002460:Cell Line; D002843:Chromatin / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000737:chemistry / Q000502:physiology*; D006801:Humans; D016297:Mutagenesis, Site-Directed; D054829:RING Finger Domains / Q000502:physiology*; D011995:Recombination, Genetic; D054875:Ubiquitination
chemical_list: D002843:Chromatin; D006657:Histones; D018398:Homeodomain Proteins; C064658:RAG-1 protein