A5020716368- Ubiquitin and proteasome pathways
- Microtubule and mitosis dynamics
- DNA Repair Mechanisms
- Fungal and yeast genetics research
- Autophagy in Disease and Therapy
- RNA and protein synthesis mechanisms
- Endoplasmic Reticulum Stress and Disease
- Genetic factors in colorectal cancer
- Microbial Metabolic Engineering and Bioproduction
- PARP inhibition in cancer therapy
- Epigenetics and DNA Methylation
- CRISPR and Genetic Engineering
- Genomics and Chromatin Dynamics
- Peptidase Inhibition and Analysis
- Bacterial Genetics and Biotechnology
- Genetics and Neurodevelopmental Disorders
- Cancer-related Molecular Pathways
- Cellular transport and secretion
- RNA Research and Splicing
- Protein Structure and Dynamics
- Protein Degradation and Inhibitors
AstraZeneca (United Kingdom)
2023-2024
The Francis Crick Institute
2020-2023
MRC Laboratory of Molecular Biology
2012-2017
Medical Research Council
2017
University of California, San Francisco
2007-2010
University of California, Davis
2004
Approximately 30% of eukaryotic proteins contain hydrophobic signals for localization to the secretory pathway. These can be mislocalized in cytosol due mutations their targeting signals, certain stresses, or intrinsic inefficiencies translocation. Mislocalized (MLPs) are protected from aggregation by Bag6 complex and degraded a poorly characterized proteasome-dependent Here, we identify ubiquitin ligase RNF126 as key component MLP degradation In vitro reconstitution fractionation studies...
Deciding a protein's fate Protein synthesis inside cells is finely balanced with protein degradation to maintain homeostasis. Shao et al. show how differential affinities and binding kinetics of three chaperones regulate the tail-anchored (TA) membrane proteins. The chaperone SGTA binds TA proteins quickly transfers them targeting factor TRC40 through C-terminal domain quality-control module BAG6. Proteins that dissociate from can either rebind or, at slower rate, be bound by latter puts on...
Unlocking novel E3 ligases for use in heterobifunctional PROTAC degraders is of high importance to the pharmaceutical industry. Over-reliance on current suite ligands used recruit could limit potential their application. To address this, potent DCAF15 were optimized using cryo-EM supported, structure-based design improve micromolar starting points. A binder, compound 24, was identified and subsequently conjugated into PROTACs against multiple targets. Following attempts degrading a number...
MutSα and MutSβ play important roles in DNA mismatch repair are linked to inheritable cancers degenerative disorders. Here, we show that MSH2 MSH3, the two components of MutSβ, bind SLX4 protein, a scaffold for assembly SLX1-SLX4-MUS81-EME1-XPF-ERCC1 (SMX) trinuclease complex. SMX promotes resolution Holliday junctions (HJs), which intermediates homologous recombinational repair. We find binds HJs stimulates their by SLX1-SLX4 or reactions dependent upon direct interactions between SLX4. In...
Kinetochores are composed of a large number protein complexes that must be properly assembled on DNA to attach chromosomes the mitotic spindle and coordinate their segregation with advance cell cycle. CBF3 is an inner kinetochore complex in budding yeast Saccharomyces cerevisiae nucleates recruitment all other proteins centromeric DNA. Skp1p Sgt1p act through core subunit, Ctf13p, required for associate To investigate contribution function, we have used combination vitro binding assays...
Our genomes harbor conserved DNA sequences, known as common fragile sites (CFSs), that are difficult to replicate and correspond regions of genome instability. Following replication stress, CFS loci give rise breaks or gaps (termed expression) where under-replicated subsequently undergoes mitotic synthesis (MiDAS). We show loss the structure-selective endonuclease GEN1 reduces expression, leading defects in MiDAS, ultrafine anaphase bridge formation, damage ensuing cell cycle due aberrant...