A5056557307- DNA Repair Mechanisms
- CRISPR and Genetic Engineering
- PARP inhibition in cancer therapy
- Genomics and Chromatin Dynamics
- Ubiquitin and proteasome pathways
- RNA and protein synthesis mechanisms
- RNA modifications and cancer
- Genetics and Neurodevelopmental Disorders
- RNA Research and Splicing
- Plant Gene Expression Analysis
- Enzyme Structure and Function
- Antibiotic Resistance in Bacteria
- Fungal and yeast genetics research
- interferon and immune responses
- Bacterial Genetics and Biotechnology
- RNA regulation and disease
- Microtubule and mitosis dynamics
- Retinal Development and Disorders
- Cancer-related Molecular Pathways
- Carcinogens and Genotoxicity Assessment
- Bioinformatics and Genomic Networks
- Plant tissue culture and regeneration
- Plant Molecular Biology Research
- Plant Virus Research Studies
- Escherichia coli research studies
Simon Fraser University
2024-2025
Lunenfeld-Tanenbaum Research Institute
2018-2024
Mount Sinai Hospital
2018-2024
University of British Columbia
2013-2022
Canada's Michael Smith Genome Sciences Centre
2013
DNA repair by homologous recombination (HR) is essential for genomic integrity, tumor suppression, and the formation of gametes. HR uses synthesis to lesions such as double-strand breaks stalled replication forks, but despite having a good understanding steps leading homology search strand invasion, we know much less mechanisms that establish recombination-associated polymerization. Here, report C17orf53/HROB an OB-fold-containing factor involved in acts recruiting MCM8-MCM9 helicase sites...
Abstract 53BP1 is a chromatin‐binding protein that promotes DNA double‐strand break repair through the recruitment of downstream effectors including RIF1, shieldin, and CST. The structural basis protein–protein interactions within 53BP1‐RIF1‐shieldin‐CST pathway are essential for its activity largely unknown. Here, we used AlphaFold2‐Multimer (AF2) to predict all possible pairwise combinations proteins this provide models seven previously characterized interactions. This analysis also...
The post-translational modification of proteins by SUMO is crucial for cellular viability and mammalian development in part due to the contribution SUMOylation genome duplication repair. To investigate mechanisms underpinning essential function SUMO, we undertook a genome-scale CRISPR/Cas9 screen probing response inhibition. This effort identified 130 genes whose disruption reduces or enhances toxicity TAK-981, clinical-stage inhibitor E1-activating enzyme. Among strongest hits, validated...
To maintain genome integrity, cells must accurately duplicate their and repair DNA lesions when they occur. uncover genes that suppress damage in human cells, we undertook flow-cytometry-based CRISPR-Cas9 screens monitored damage. We identified 160 whose mutation caused spontaneous damage, a list enriched essential genes, highlighting the importance of genomic integrity for cellular fitness. also 227 replication-perturbed cells. Among characterized, discovered deoxyribose-phosphate aldolase...
Atg17, in complex with Atg29 and Atg31, constitutes a key module of the Atg1 kinase signaling functions as an important organizer phagophore assembly site yeast Saccharomyces cerevisiae. We have determined three-dimensional reconstruction full S. cerevisiae Atg17-Atg31-Atg29 by single-particle electron microscopy. Our structure shows that is dimeric adopts relatively rigid extended "S-shape" architecture end-to-end distance approximately 345 Å. Subunit mapping analysis indicated Atg17...
Conserved from yeast to humans, the NuA4 histone acetyltransferase is a large multisubunit complex essential for cell viability through regulation of gene expression, genome maintenance, metabolism, and fate during development stress. How different subunits work in concert with one another perform these diverse functions remains unclear, addressing this central question requires comprehensive understanding NuA4's molecular architecture subunit organization. We have determined structure fully...
Abstract Chromatin Assembly Complex 1 (CAF-1) is a major histone chaperone involved in deposition of H3 and H4 into nucleosome. CAF-1 composed three subunits; p150, p60 p48 for human Cac1, Cac2 Cac3 yeast. Despite its central role chromatin formation, structural features the full complex with histones other chaperones have not been well characterized. Here, we dissect molecular architecture yeast (yCAF-1) by cross-linking mass spectrometry (XL-MS) negative stain single-particle electron...
Abstract The KEOPS complex, which is conserved across archaea and eukaryotes, composed of four core subunits; Pcc1, Kae1, Bud32 Cgi121. crucial for the fitness all organisms examined. In humans, pathogenic mutations in genes lead to Galloway–Mowat syndrome, an autosomal-recessive disease causing childhood lethality. Kae1 catalyzes universal essential tRNA modification N 6 -threonylcarbamoyl adenosine, but precise roles other subunits remain enigma. Here we show using structure-guided studies...
RS1, also known as retinoschisin, is a disulphide-linked, discoidin domain containing homo-oligomeric protein that plays crucial role in maintaining the cellular and synaptic organization of retina. This highlighted by finding over 130 mutations RS1 cause X-linked retinoschisis, retinal degenerative disease characterized splitting cell layers, disruption photoreceptor–bipolar synapses, degeneration photoreceptors, severe loss central vision. In this study, we investigated arrangement...
BRCA1/2 -mutated cancer cells must adapt to the genome instability caused by their deficiency in homologous recombination. Identifying and targeting these adaptive mechanisms may provide new therapeutic strategies. Here we present results of genome-scale CRISPR/Cas9-based synthetic lethality screens isogenic pairs BRCA1- BRCA2-deficient that identified gene encoding CIP2A as essential a wide range BRCA1 - BRCA2 cells. Unlike PARP inhibition, CIP2A-deficiency does not cause accumulation...
ABSTRACT Type III secretion systems (T3SSs) are central virulence mechanisms used by a variety of Gram-negative bacteria to inject effector proteins into host cells. The needle polymer is an essential part the T3SS that provides continuous channel cytoplasm. It has been shown for few T3SSs two chaperones stabilize protein within bacterial cytosol prevent its premature polymerization. In this study, we characterized enteropathogenic Escherichia coli (EPEC) EscF. We found Orf2 and Orf29,...
Abstract 53BP1 is a chromatin-binding DNA repair protein that promotes double-strand break through recruitment of downstream effectors including RIF1, shieldin, and CST. The structural basis the protein-protein interactions within 53BP1-RIF1-shieldin-CST pathway are essential for its activity largely unknown. Here we used AlphaFold2-Multimer (AF2) to predict all possible pairwise combinations proteins this provide models seven previously characterized interactions. This analysis also...
ABSTRACT Double-stranded RNAs (dsRNAs) produced during viral infections are recognized by the innate immune sensor protein kinase R (PKR), triggering a host translation shutoff that inhibits replication and propagation. Given harmful effects of uncontrolled PKR activation, cells must tightly regulate to ensure its activation occurs only in response infections, not endogenous dsRNAs. Here, we use CRISPR-Translate, FACS-based genome-wide CRISPR-Cas9 knockout screening method exploits levels as...
Summary The chromatin-binding protein 53BP1 promotes DNA repair by orchestrating the recruitment of downstream effectors including PTIP, RIF1 and shieldin to double-strand break sites. While how PTIP recognizes is known, molecular details damage sites remains undefined. Here, we report that a phosphopeptide-binding directly interacts with three phosphorylated epitopes. RIF1-binding on share an essential LxL motif followed two closely apposed residues. Simultaneous mutation these abrogates...