CUL4-Based Ubiquitin Ligases in Chromatin Regulation: An Evolutionary Perspective

Cells, Journal Year: 2025, Volume and Issue: 14(2), P. 63 - 63

Published: Jan. 7, 2025

Ubiquitylation is a post-translational modification that modulates protein function and stability. It orchestrated by the concerted action of three types enzymes, with substrate specificity governed ubiquitin ligases (E3s), which may exist as single proteins or part multi-protein complexes. Although Cullin (CUL) lack intrinsic enzymatic activity, they participate in formation active ligase complexes, known Cullin-Ring Ligases (CRLs), through their association ROC1 ROC2, along adaptor receptor proteins. Mammalian genomes encode several CUL (CUL1-9), each contributing to distinct CRLs. Among these proteins, CUL1, CUL3, CUL4 are believed be most ancient evolutionarily conserved from yeast mammals, uniquely duplicated vertebrates. Genetic evidence strongly implicates CUL4-based (CRL4s) chromatin regulation across various species suggests that, vertebrates, CRL4s have also acquired cytosolic role, facilitated cytosol-localizing paralog CUL4. Substrates identified biochemical studies elucidated molecular mechanisms regulate processes. The substantial body knowledge on biology amassed over past two decades provides unique opportunity explore functional evolution CRL4. In this review, we synthesize available structural, genetic, data CRL4 model organisms discuss novel functions CRL4s.

Language: Английский

HIV Vpr activates a nucleolar-specific ATR pathway to degrade the nucleolar stress sensor CCDC137

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 11, 2024

ABSTRACT The lentiviral accessory protein Vpr engages an extensive network of cellular pathways to drive diverse host consequences. Of its many phenotypes, CRL4A-E3 ubiquitin ligase complex co-option, DNA damage response (DDR) engagement, and G2/M arrest are conserved thus proposed be functionally important. How effects these functions whether they explain how dysregulates additional remain unclear. Here we leverage the ability deplete nucleolar CCDC137 understand Vpr-induced DDR activation impacts processes. We characterize as indirect target whose degradation does not correlate with arrest. Yet, is among from pandemic HIV-1 related SIVcpz/SIVgor, it triggered by genomic insults that activate a ATR pathway in manner similar camptothecin. determine causes ATR-dependent features stress degradation, including redistribution proteins, altered morphology, repressed ribosome biogenesis. Together, this data distinguishes non-canonical may serve sensor disruption, doing so, identifies novel role for stress. GRAPHICAL

Language: Английский