98%
921
2 minutes
20
The duration of a woman's reproductive period is determined by the size and persistence of a dormant oocyte pool. Specific oocyte genes are essential for follicle maintenance and female fertility. The mechanisms that regulate the expression of these genes are poorly understood. We found that a cullin-ring finger ligase-4 (CRL4) complex was crucial in this process. Oocyte-specific deletion of the CRL4 linker protein DDB1 or its substrate adaptor VPRBP (also known as DCAF1) caused rapid oocyte loss, premature ovarian insufficiency, and silencing of fertility maintaining genes. CRL4(VPRBP) activates the TET methylcytosine dioxygenases, which are involved in female germ cell development and zygote genome reprogramming. Hence, CRL4(VPRBP) ubiquitin ligase is a guardian of female reproductive life in germ cells and a maternal reprogramming factor after fertilization.
Download full-text PDF |
Source |
---|---|
http://dx.doi.org/10.1126/science.1244587 | DOI Listing |
Mol Cell
August 2025
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address:
Glutarimide analogs, such as thalidomide, redirect the E3 ubiquitin ligase CRL4 to induce degradation of certain zinc finger (ZF) proteins. Although the core structural motif recognized by CRBN has been characterized, it does not fully explain substrate specificity. To explore the role of residues adjacent to this core motif, we constructed a comprehensive ZF reporter library of 9,097 reporters derived from 1,655 human ZF proteins and conducted a library-on-library screen with 29 glutarimide analogs to identify compounds that collectively degrade 38 ZF reporters.
View Article and Find Full Text PDFCell Death Discov
August 2025
Department of Reproductive Medicine, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
The incidence of female infertility is a growing worldwide concern and a leading cause of population decline. Therefore, understanding the pathogenesis of infertility is of utmost importance. DDB1 and CUL4 Associated Factor 13 (DCAF13) is a significant component of the CRL4 E3 ubiquitin ligase complex responsible for recognizing substrates and degrading them after polyubiquitylation.
View Article and Find Full Text PDFCommun Biol
July 2025
Structural Genomics Consortium, University of Toronto, Toronto, ON, Canada.
Human DCAF1 is a multidomain protein that plays a critical role in protein homeostasis. Its WDR domain functions as a substrate recruitment module for RING-type CRL4 and HECT family EDVP E3 ubiquitin ligases, enabling the ubiquitination and proteasomal degradation of specific substrates. DCAF1's activity has been implicated in cell proliferation and is documented to promote tumorigenesis.
View Article and Find Full Text PDFInt J Biol Macromol
July 2025
Anhui Province Key Laboratory of Horticultural Crop Quality Biology, School of Horticulture, Anhui Agricultural University, Hefei 230036, China. Electronic address:
Plants have evolved intricate regulatory mechanisms to balance growth and defense. In particular, the UV-damaged DNA-binding protein 1 (DDB1), which can form an E3 ubiquitin ligase with CUL4 (Cullin4-Ring Ligase, CRL4), is widely involved in plant growth and response to adversity. The tomato spontaneous SlDDB1-defective high pigment 1 (hp1) mutant manifests significantly increased plastid level and pigments accumulation, but the underlying molecular mechanism remains unclear.
View Article and Find Full Text PDFACS Chem Biol
July 2025
Guangdong-Hong Kong-Macao Joint Laboratory for New Drug Screening, School of Pharmacy, The Chinese University of Hong Kong, Sha Tin, Hong Kong.
O-Linked β--acetylglucosamine-modification (O-GlcNAcylation) is an important post-translational modification (PTM), yet dissecting its protein-specific functions has remained challenging. Here, we applied our previously reported chemical biology tool, the O-GlcNAcylation Targeting Chimera (OGTAC), to specifically induce O-GlcNAcylation of the casein kinase II subunit α (CK2α) at Ser347 in living cells. We found that this targeted O-GlcNAcylation destabilized CK2α through ubiquitin-proteasome degradation and enhanced its interaction with cereblon (CRBN).
View Article and Find Full Text PDF