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

---

Cell competition: emerging signaling and unsolved questions

FEBS Letters, Journal Year: 2024, Volume and Issue: 598(4), P. 379 - 389

Published: Feb. 1, 2024

Multicellular communities have an intrinsic mechanism that optimizes their structure and function via cell–cell communication. One of the driving forces for such self‐organization multicellular system is cell competition, elimination viable unfit or deleterious cells interaction. Studies in Drosophila mammals identified multiple mechanisms competition caused by different types mutations cellular changes. Intriguingly, recent studies found “losers” commonly show reduced protein synthesis. In , reduction synthesis levels loser phosphorylation translation initiation factor eIF2α a bZip transcription Xrp1. Given variety stresses converge on thus global inhibition synthesis, may be machinery fitness removing stressed cells. this review, we summarize discuss emerging signaling critical unsolved questions, as well role competition.

Language: Английский

---

Cell polarity and extrusion: How to polarize extrusion and extrude misspolarized cells?

Current topics in developmental biology/Current Topics in Developmental Biology, Journal Year: 2023, Volume and Issue: unknown, P. 131 - 167

Published: Jan. 1, 2023

Language: Английский

---

Ribosomal protein mutations and cell competition: autonomous and nonautonomous effects on a stress response

Genetics, Journal Year: 2023, Volume and Issue: 224(3)

Published: June 2, 2023

Abstract Ribosomal proteins (Rps) are essential for viability. Genetic mutations affecting Rp genes were first discovered in Drosophila, where they represent a major class of haploinsufficient mutations. One mutant copy gives rise to the dominant “Minute” phenotype, characterized by slow growth and small, thin bristles. Wild-type (WT) Minute cells compete mosaics, that is, Rp+/− preferentially lost when their neighbors wild-type genotype. Many features gene haploinsufficiency (i.e. phenotypes) mediated transcriptional program. In reduced translation under control Xrp1, bZip-domain transcription factor induced leads ultimately phosphorylation eIF2α consequently inhibition most translation. phenotypes also transcriptionally yeast mammals. mammals, Impaired Ribosome Biogenesis Checkpoint activates p53. Recent findings link other cellular stresses, including DNA damage response endoplasmic reticulum stress. We suggest cell competition results from nonautonomous inputs stress responses, bringing decisions between adaptive apoptotic outcomes influence nearby cells. eliminates aneuploid which loss chromosome haploinsufficiency. The effects on whole organism, flies or humans with Diamond-Blackfan Anemia, may be inevitable consequences pathways useful eliminating individual mosaics. Alternatively, apparently deleterious organism might adaptive, preventing even more detrimental outcomes. example, p53 activation appears suppress oncogenic

Language: Английский

---

Loss of Paip1 causes translation reduction and induces apoptotic cell death through ISR activation and Xrp1

Cell Death Discovery, Journal Year: 2023, Volume and Issue: 9(1)

Published: Aug. 5, 2023

Regulation of protein translation initiation is tightly associated with cell growth and survival. Here, we identify Paip1, the Drosophila homolog factor PAIP1, analyze its role during development. Through genetic analysis, find that loss Paip1 causes reduced pupal lethality. Furthermore, tissue specific knockdown results in apoptotic death wing imaginal disc. depletion leads to increased proteotoxic stress activation integrated response (ISR) pathway. Mechanistically, show promotes phosphorylation eIF2α via kinase PERK, leading death. Moreover, upregulates transcription gene Xrp1, which contributes phosphorylation. We further an increase Xrp1 mediated by 5'UTR. These findings uncover a novel mechanism links impairment homeostasis establish ISR promoting

Language: Английский

---