CRL4^DCAF1/VprBP E3 ubiquitin ligase controls ribosome biogenesis, cell proliferation, and development

Area of Science:

• Cell Biology
• Molecular Biology
• Genetics

Background:

• DCAF1 is an evolutionarily conserved protein crucial for cell proliferation and development.
• It functions as a substrate receptor for the CRL4 E3 ubiquitin ligase complex.
• The precise molecular mechanisms underlying DCAF1's roles remain largely unknown.

Purpose of the Study:

• To elucidate the molecular basis of DCAF1's function in cell proliferation and development.
• To identify substrates of the CRL4^DCAF1 ligase complex.
• To understand the impact of DCAF1 loss on cellular processes.

Main Methods:

• Generating and analyzing DCAF1 loss models in various tissues and cell types (T cells, MEFs).
• Utilizing inducible DCAF1 loss to study effects on proliferating versus quiescent cells.
• Identifying PWP1 as a CRL4^DCAF1 substrate using biochemical approaches.
• Assessing rRNA processing, ribosome biogenesis, and p53 activation pathways.

Main Results:

• DCAF1 loss leads to selective elimination of proliferating cells, causing perinatal lethality and organ defects.
• PWP1 was identified as a substrate, and its accumulation upon DCAF1 loss impairs ribosome biogenesis.
• Manipulating PWP1 levels mimicked or rescued DCAF1 loss-associated defects.
• DCAF1 loss resulted in increased free RPL11, leading to p53 activation via MDM2.

Conclusions:

• DCAF1 plays a critical role in ribosome biogenesis.
• DCAF1's function in ribosome biogenesis provides a molecular basis for its control over cell proliferation and development.
• The CRL4^DCAF1 ligase regulates PWP1 stability, impacting ribosome production and cell cycle control.