Abstract
The periodic destruction of RAG-2 at the G1-to-S transition couples V(D)J recombination to the G0 and G1 cell cycle phases and coordinates RAG-mediated DNA cleavage with DNA repair by nonhomologous end joining. To define the mechanism by which this occurs, we reproduced cell cycle-dependent regulation of the V(D)J recombinase in a cell-free system. The ubiquitin-proteasomal pathway carries out destruction of RAG-2 in lysates of S phase cells and during S phase in vivo. Remarkably, the Skp2-SCF ubiquitin ligase, which plays a central role in cell cycle regulation through the destruction of p27, mediates ubiquitylation of RAG-2 in vitro and degradation of RAG-2 in vivo. The regulation of antigen receptor gene assembly by Skp2-SCF provides an unexpected and direct mechanistic link between DNA recombination and the cell cycle.
Original language | English (US) |
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Pages (from-to) | 699-709 |
Number of pages | 11 |
Journal | Molecular cell |
Volume | 18 |
Issue number | 6 |
DOIs | |
State | Published - Jun 10 2005 |
Externally published | Yes |
Funding
We thank Dr. H. Zhang for baculoviruses encoding Skp2 and Cul1 and Dr. D. Bohmann for the ubiquitin-HA construct. This work was supported by the National Cancer Institute and the Howard Hughes Medical Institute.
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology