Abstract
The ubiquitin-proteolytic system controls the stability of proteins in space and time. In this study, using a temperature-sensitive mutant allele of the cul-2 gene, we show that CRL2LRR-1 (CUL-2 RING E3 ubiquitin-ligase and the Leucine Rich Repeat 1 substrate recognition subunit) acts at multiple levels to control germline development. CRL2LRR-1 promotes germ cell proliferation by counteracting the DNA replication ATL-1 checkpoint pathway. CRL2LRR-1 also participates in the mitotic proliferation/meiotic entry decision, presumably controlling the stability of meiotic promoting factors in the mitotic zone of the germline. Finally, CRL2LRR-1 inhibits the first steps of meiotic prophase by targeting in mitotic germ cells degradation of the HORMA domain-containing protein HTP-3, required for loading synaptonemal complex components onto meiotic chromosomes. Given its widespread evolutionary conservation, CUL-2 may similarly regulate germline development in other organisms as well.
Highlights
The ubiquitin-proteolytic system has emerged as a central mechanism to regulate protein turnover spatially and temporally [1,2]
Factors regulating the balance between germline stem cell selfrenewal and meiotic differentiation ensure germline homeostasis, whereas disruption of these regulatory mechanisms can lead to sterility or cancer
We show that the ubiquitin-proteolytic system (UPS), which selectively targets regulatory proteins for proteasomal degradation, controls germline development by acting at three different levels
Summary
The ubiquitin-proteolytic system has emerged as a central mechanism to regulate protein turnover spatially and temporally [1,2]. In this system, ubiquitin, a small polypeptide of 76 amino acids, is covalently linked to a target protein through an enzymatic cascade, and the assembly of a poly-ubiquitin chain typically specifies that target protein for rapid degradation via the 26S proteasome [3]. The assembly of poly-ubiquitin chains can occur at different lysine residues within ubiquitin, with conjugation at lysines 11 and 48 typically leading to proteasomal degradation [8,9,10,11–12]
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