| First Author | Kassmeier MD | Year | 2012 |
| Journal | EMBO J | Volume | 31 |
| Issue | 4 | Pages | 945-58 |
| PubMed ID | 22157821 | Mgi Jnum | J:181758 |
| Mgi Id | MGI:5314150 | Doi | 10.1038/emboj.2011.455 |
| Citation | Kassmeier MD, et al. (2012) VprBP binds full-length RAG1 and is required for B-cell development and V(D)J recombination fidelity. EMBO J 31(4):945-58 |
| abstractText | The N-terminus of full-length RAG1, though dispensable for RAG1/2 cleavage activity, is required for efficient V(D)J recombination. This region supports RING E3 ubiquitin ligase activity in vitro, but whether full-length RAG1 functions as a single subunit or a multi-subunit E3 ligase in vivo is unclear. We show the multi-subunit cullin RING E3 ligase complex VprBP/DDB1/Cul4A/Roc1 associates with full-length RAG1 through VprBP. This complex is assembled into RAG protein-DNA complexes, and supports in-vitro ubiquitylation activity that is insensitive to RAG1 RING domain mutations. Conditional B lineage-specific VprBP disruption arrests B-cell development at the pro-B-to-pre-B cell transition, but this block is bypassed by expressing rearranged immunoglobulin transgenes. Mice with a conditional VprBP disruption show modest reduction of D-J(H) rearrangement, whereas V(H)-DJ(H) and V(kappa)-J(kappa) rearrangements are severely impaired. D-J(H) coding joints from VprBP-insufficent mice show longer junctional nucleotide insertions and a higher mutation frequency in D and J segments than normal. These data suggest full-length RAG1 recruits a cullin RING E3 ligase complex to ubiquitylate an unknown protein(s) to limit error-prone repair during V(D)J recombination. |
