A5067683892- DNA Repair Mechanisms
- Autophagy in Disease and Therapy
- Ubiquitin and proteasome pathways
- Fungal and yeast genetics research
- Endoplasmic Reticulum Stress and Disease
- Mitochondrial Function and Pathology
- Parkinson's Disease Mechanisms and Treatments
- Plant Molecular Biology Research
- Plant nutrient uptake and metabolism
- Cancer-related gene regulation
- Epigenetics and DNA Methylation
- Cellular transport and secretion
- Microtubule and mitosis dynamics
- Genomics and Chromatin Dynamics
- Lysosomal Storage Disorders Research
- Plant Disease Resistance and Genetics
- Genetics and Neurodevelopmental Disorders
MRC Protein Phosphorylation and Ubiquitylation Unit
2020-2024
University of Dundee
2020-2024
Medical Research Council
2022
Harvard University
2022
Cancer Research UK
2020
Cold Spring Harbor Laboratory
2020
Institute of Predictive and Personalized Medicine of Cancer
2016
Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol
2016
Loss-of-function mutations in PTEN-induced kinase 1 (PINK1) are a frequent cause of early-onset Parkinson’s disease (PD). Stabilization PINK1 at the translocase outer membrane (TOM) complex damaged mitochondria is critical for its activation. The mechanism how activated TOM unclear. Here, we report that co-expression human and all seven subunits Saccharomyces cerevisiae sufficient We use this reconstitution system to systematically assess role each subunit toward unambiguously demonstrate...
The eukaryotic replisome assembles around the CMG helicase, which stably associates with DNA replication forks throughout elongation. When terminates, is ubiquitylated on its Mcm7 subunit and disassembled by Cdc48/p97 ATPase. Until now, regulation that restricts ubiquitylation to termination was unknown, as mechanism of disassembly. By reconstituting these processes purified budding yeast proteins, we show tightly repressed elongation Y-shaped structure forks. Termination removes repressive...
The p97/Cdc48 ATPase and its ubiquitin receptors Ufd1-Npl4 are essential to unfold ubiquitylated proteins in many areas of eukaryotic cell biology. In yeast, Cdc48-Ufd1-Npl4 is controlled by a quality control mechanism, whereby substrates must be conjugated at least five ubiquitins. Here, we show that mammalian p97-UFD1-NPL4 governed complex interplay between additional p97 cofactors the number Using reconstituted assays for disassembly CMG (Cdc45-MCM-GINS) helicase human p97-UFD1-NPL4,...
DNA hypomethylation at repetitive elements accounts for the genome-wide common in cancer, including colorectal cancer (CRC). We identified a pericentromeric repeat element called SST1 frequently hypomethylated (>5% demethylation compared with matched normal tissue) several cancers, 28 of 128 (22%) CRCs. somatic associated genome damage, especially tumors wild-type TP53. Seven percent CRCs exhibited higher ("severe") level (≥10%) that co-occurred TP53 mutations. correlated distinct histone...
Cullin ubiquitin ligases drive replisome disassembly during DNA replication termination. In worm, frog and mouse cells, CUL2LRR1 is required to ubiquitylate the MCM7 subunit of CMG helicase. Here, we show that cullin also CMG-MCM7 ubiquitylation in human thereby making helicase into a substrate for p97 unfoldase. Using purified proteins, including panel E2 ubiquitin-conjugating enzymes, have reconstituted ubiquitylation, dependent upon neddylated CUL2LRR1. The reaction highly specific...
Abstract Loss of function mutations in PTEN-induced kinase 1 (PINK1) are a frequent cause early-onset Parkinson’s disease (PD). Stabilisation PINK1 at the Translocase Outer Membrane (TOM) complex damaged mitochondria is critical step for its activation. To date mechanism how activated TOM unclear. Herein we report co-expression human and all seven subunits Saccharomyces cerevisiae sufficient We use this reconstitution system to systematically assess role each subunit towards unambiguously...