A5071970922- CRISPR and Genetic Engineering
- DNA Repair Mechanisms
- Genetics and Neurodevelopmental Disorders
- Ubiquitin and proteasome pathways
- Cancer-related gene regulation
- Wnt/β-catenin signaling in development and cancer
- Cancer-related Molecular Pathways
- PARP inhibition in cancer therapy
- Genomics and Chromatin Dynamics
- Polyamine Metabolism and Applications
- Insect Resistance and Genetics
- Biochemical and Molecular Research
- Peptidase Inhibition and Analysis
- Protein Degradation and Inhibitors
- Endoplasmic Reticulum Stress and Disease
- Autophagy in Disease and Therapy
- RNA Interference and Gene Delivery
- Toxoplasma gondii Research Studies
- Fibroblast Growth Factor Research
- Chromatin Remodeling and Cancer
Lunenfeld-Tanenbaum Research Institute
2022-2024
Mount Sinai Hospital
2022-2024
University of Guelph
2023-2024
Abstract Tumor suppressor p53 (TP53) is frequently mutated in cancer, often resulting not only loss of its tumor-suppressive function but also acquisition dominant-negative and even oncogenic gain-of-function traits. While wild-type levels are tightly regulated, mutants typically stabilized tumors, which crucial for their properties. Here, we systematically profiled the factors that regulate protein stability mutant using marker-based genome-wide CRISPR screens. Most regulators mutants,...
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...
The WEE1 kinase negatively regulates CDK1/2 to control DNA replication and mitotic entry. Genetic factors that determine sensitivity inhibitors (WEE1i) are largely unknown. A genome-wide insertional mutagenesis screen revealed mutation of EIF2A, a translation regulator, sensitized WEE1i. Mechanistically, WEE1i treatment triggers translational shut-down, which is lethal in combination with the reduced EIF2AKO cells. CRISPR-Cas9 inactivation integrated stress response (ISR) kinases GCN1/2...
Wnt signaling is a crucial developmental pathway involved in early development as well stem-cell maintenance adults and its misregulation leads to numerous diseases. Thus, understanding the regulation of this becomes vitally important. Axin2 Nkd1 are widely utilized negative feedback regulators where functions destabilize cytoplasmic β-catenin, inhibit nuclear localization β-catenin. Here, we set out further understand how regulate by creating
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 DNA replication stress is a threat to genome integrity. The large SNF2-family of ATPases participates in preventing and mitigating by employing their ATP-driven motor remodel or DNA-bound proteins. To understand the contribution these maintenance, we undertook CRISPR-based synthetic lethality screens with three SNF2-type ATPases: SMARCAL1, ZRANB3 HLTF. Here show that SMARCAL1 displays profound lethal interaction FANCM , another ATP-dependent translocase involved stability. Their...
Abstract The post-translational modification of proteins by ubiquitin and ubiquitin-like polypeptides controls multiple cellular processes including the abundance a large fraction proteome. We applied genome-scale CRISPR/Cas9 screens to elucidate genetic architecture response inhibition ubiquitin, NEDD8 SUMO conjugation pathways as well p97/VCP segregase. This effort identified 395 genes whose disruption alters fitness human cells when faced with perturbations in these pathways. validated...
Abstract Wnt signaling is a crucial developmental pathway involved in early development as well stem cell maintenance adults and its misregulation leads to numerous diseases. Thus, understanding the regulation of this becomes vitally important. Axin2 Nkd1 are widely utilized negative feedback regulators where functions destabilize cytoplasmic β-catenin, inhibit nuclear localization β-catenin. Here, we set out further understand how regulate by creating axin2 -/- , nkd1 single mutants ;...
Abstract To maintain genome integrity, cells must avoid DNA damage by ensuring the accurate duplication of and having efficient repair signaling systems that counteract genome-destabilizing potential lesions. uncover genes pathways suppress in human cells, we undertook genome-scale CRISPR/Cas9 screens monitored levels absence or presence replication stress. We identified 160 RKO whose mutation caused high exogenous genotoxic treatment. This list was highly enriched essential genes,...