| Autor: |
Kumar, Sushil, Kassmeier, Michele D., Raval, Prafulla, Jackson, Sarah, Ciborowski, Pawel, Palmer, Victoria L., Swanson, Patrick C., Mondal, Koushik, Anderson, Dirk K., Perry, Greg A., Xiong, Yue |
| Jazyk: |
angličtina |
| Rok vydání: |
2012 |
| DOI: |
10.17615/xtpr-cx36 |
| Popis: |
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–JH rearrangement, whereas VH–DJH and Vκ–Jκ rearrangements are severely impaired. D–JH 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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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