Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:3.1.30.2 (
endonuclease
)
18,621
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
The assembly of Ig genes in developing B lymphocytes by V(D)J recombination is initiated by the RAG1-RAG2
endonuclease
complex. We previously identified an interaction between RAG1 and viral protein R binding protein (VprBP) (also known as DNA damage binding protein 1 cullin 4-associated factor 1 [DCAF1]), a substrate receptor for the cullin 4-really interesting new gene (RING) E3 ubiquitin ligase (CRL4). We report in this article that in mice, B cell-intrinsic loss of VprBP increases
RAG1 protein
levels and disrupts expression of the endoribonuclease Dicer, which is essential for microRNA maturation.
Rag1/2
transcription is known to be derepressed by loss of microRNA-mediated suppression of phosphatase and tensin homolog, raising the possibility that the elevated level of RAG1 observed in VprBP-deficient B cells is caused indirectly by the loss of Dicer. However, we show that VprBP restrains RAG1 expression posttranscriptionally and independently of Dicer. Specifically, loss of VprBP stabilizes
RAG1 protein
, which we show is normally degraded via a mechanism requiring both 20S proteasome and cullin-RING E3 ubiquitin ligase activity. Furthermore, we show that RAG1 stabilization through small molecule inhibition of cullin-RING E3 ubiquitin ligase activation promotes V(D)J recombination in a murine pre-B cell line. Thus, in addition to identifying a role for VprBP in maintaining Dicer levels in B cells, our findings reveal the basis for RAG1 turnover and provide evidence that the CRL4
VprBP(DCAF1)
complex functions to maintain physiological levels of V(D)J recombination.
...
PMID:VprBP (DCAF1) Regulates RAG1 Expression Independently of Dicer by Mediating RAG1 Degradation. 2992 75
