A5021559502- RNA Research and Splicing
- MicroRNA in disease regulation
- RNA Interference and Gene Delivery
- Heat shock proteins research
- RNA and protein synthesis mechanisms
- RNA modifications and cancer
- DNA Repair Mechanisms
- Genetic factors in colorectal cancer
- CAR-T cell therapy research
- Endoplasmic Reticulum Stress and Disease
- Ubiquitin and proteasome pathways
- CRISPR and Genetic Engineering
- thermodynamics and calorimetric analyses
- Genomics and Chromatin Dynamics
- Bioinformatics and Genomic Networks
- Genetics and Neurodevelopmental Disorders
- ATP Synthase and ATPases Research
- Epigenetics and DNA Methylation
- Cancer-related gene regulation
- Genetics, Aging, and Longevity in Model Organisms
- FOXO transcription factor regulation
- Nerve injury and regeneration
- PI3K/AKT/mTOR signaling in cancer
- Ferroptosis and cancer prognosis
- Autophagy in Disease and Therapy
Northwestern University
2017-2025
Robert H. Lurie Comprehensive Cancer Center of Northwestern University
2021-2024
National Cancer Institute
2018
Whitehead Institute for Biomedical Research
2011-2016
Howard Hughes Medical Institute
2013-2015
Massachusetts Institute of Technology
2013-2015
Ludwig Cancer Research
2006-2013
University of California, San Diego
2006-2010
Hospital Santa Caterina
2010
Bergen Kommune
2010
Heat-shock factor 1 (HSF1) is the master transcriptional regulator of cellular response to heat and a wide variety other stressors. We previously reported that HSF1 promotes survival proliferation malignant cells. At this time, however, clinical prognostic significance in cancer unknown. To address issue breast samples from 1,841 participants Nurses’ Health Study were scored for levels nuclear HSF1. Associations status with parameters outcomes investigated by Kaplan–Meier analysis Cox...
The ribosome is centrally situated to sense metabolic states, but whether its activity, in turn, coherently rewires transcriptional responses unknown. Here, through integrated chemical-genetic analyses, we found that a dominant effect of blocking protein translation cancer cells was inactivation heat shock factor 1 (HSF1), multifaceted regulator the heat-shock response and many other cellular processes essential for anabolic metabolism, proliferation, tumorigenesis. These analyses linked...
Significance Prion proteins provide the best-understood mode for protein-based molecular memory. Since their discovery in mammals, prions have been identified diverse organisms including fungi, Aplysia , and Drosophila but not plant kingdom. Applying methods we used to uncover yeast prions, nearly 500 Arabidopsis that harbor potential prion-like domains (PrDs). At least one of these domains, Luminidependens PrD, had some classical characteristics prion when tested experimentally yeast,...
Significance Although hormonal therapies for estrogen receptor-positive (ER+) breast cancer make up the earliest, and arguably most effective, “molecularly targeted” anticancer drugs, continued progress in controlling metastatic disease has been slow. Heterogeneity complexity of signaling advanced cancers have frustrated efforts to prevent rapid evolution resistance therapies, as well kinase inhibitors other agents. On basis earlier work defining role heat shock protein 90 (HSP90)...
The Lac repressor-operator interaction was used as a reversible DNA end-blocking system in conjunction with an IAsys biosensor instrument (Thermo Affinity Sensors), which detects total internal reflectance and allows monitoring of binding dissociation real time, order to develop for studying the ability mismatch repair proteins move along DNA. MSH2-MSH6 complex bound mispaired base found be converted by ATP form that showed rapid sliding via ends also slow, direct from In contrast, pair...
Proteasomes are central regulators of protein homeostasis in eukaryotes. Proteasome function is vulnerable to environmental insults, cellular imbalance and targeted pharmaceuticals. Yet, mechanisms that cells deploy counteract inhibition this regulator little understood. To find such mechanisms, we reduced flux through the proteasome point toxicity with specific inhibitors performed genome-wide screens for mutations allowed survive. Counter expectation, reducing expression individual...
Escherichia coli MutS forms a mispair-dependent ternary complex with MutL that is essential for initiating mismatch repair (MMR) but structurally uncharacterized, in part owing to its dynamic nature. Here, we used hydrogen/deuterium exchange mass spectrometry and other methods identify region the connector domain (domain II) of binds required formation MMR. A conserved Msh2, eukaryotic homolog, was Msh2-Msh6-Mlh1-Pms1 complex. These data indicate Msh2 contains interface binding Mlh1-Pms1,...
Lynch syndrome (hereditary nonpolypsis colorectal cancer or HNPCC) is a common predisposition syndrome. Predisposition to in this results from increased accumulation of mutations due defective mismatch repair (MMR) caused by mutation one the genes MLH1, MSH2, MSH6 PMS2/scPMS1. To better understand function Mlh1-Pms1 MMR, we used Saccharomyces cerevisiae identify six pms1 (pms1-G683E, pms1-C817R, pms1-C848S, pms1-H850R, pms1-H703A and pms1-E707A) that were weakly dominant wild-type cells,...
Abstract Splicing alterations are common in diseases such as cancer, where mutations splicing factor genes frequently responsible for aberrant splicing. Here we present an alternative mechanism regulation T-cell acute lymphoblastic leukemia (T-ALL) that involves posttranslational stabilization of the machinery via deubiquitination. We demonstrate there extensive exon skipping changes disease, affecting proteasomal subunits, cell-cycle regulators, and RNA machinery. serine/arginine-rich...
Genetic coessentiality analysis, a computational approach which identifies genes sharing common effect on cell fitness across large-scale screening datasets, has emerged as powerful tool to identify functional relationships between human genes. However, widespread implementation of study individual and pathways is limited by systematic biases in existing approaches accessibility barriers for investigators without expertise. We created FIREWORKS, method interactive the construction...
Heat shock factor 1 (HSF1) is well known for its role in the heat response (HSR), where it drives a transcriptional program comprising protein (HSP) genes, and tumorigenesis, HSPs many noncanonical target genes that support malignancy. Here, we find HSF2, an HSF1 paralog with no substantial HSR, physically functionally interacts across diverse types of cancer. HSF2 have notably similar chromatin occupancy regulate common set include both targets roles critical supporting Loss either or...
Proper histone gene expression is critical to cell viability and maintaining genomic integrity. Multiple genes organized into three loci encode for replication coupled core linker histones. Histone transcript processing orchestrated in the locus body (HLB) within nucleus. We identified human CRAMP1 as a selective regulator of H1 expression. recruited HLB RPE1 hTERT cells. Affinity purification shows that physically associates component GON4L (a.k.a. YARP). show PAH domains interact with...
The de novo purine synthesis pathway is fundamental for nucleic acid production and cellular energetics, yet the role of mitochondrial metabolism in modulating this process remains underexplored. In many cancers, metabolic reprogramming supports rapid proliferation survival, but specific contributions tricarboxylic (TCA) cycle enzymes to nucleotide biosynthesis are not fully understood. Here, we demonstrate that TCA enzyme succinate dehydrogenase (SDH) essential maintaining optimal normal...
Cancer encompasses a range of severe diseases characterized by uncontrolled cell growth and the potential for metastasis. Understanding mechanism underlying tumorigenesis has been central focus cancer research. Self-propagating protein aggregates, known as prions, are linked to various biological functions diseases, particularly those related mammalian neurodegeneration. However, it remains unclear whether prion-like mechanisms contribute cancer. Using combined approach algorithmic...
Significance We developed and applied nanogold labels for DNA complexes with proteins examined by small angle X-ray scattering (SAXS) to follow conformations acting in error detection the mismatch repair (MMR) system solution. This technique can examine short or long pieces of most solution conditions, including those closest cellular environments. Thus, we expect be useful many biologically important systems involving conformations. Specifically, reveal bending followed straightening...
The genus Orthopoxviridae contains a diverse group of human pathogens including monkeypox, smallpox and vaccinia. These viruses are presumed to be less dependent on host functions than other DNA because they have large genomes replicate in the cytoplasm, but detailed understanding factors required by orthopoxviruses is lacking. To address this topic, we performed an unbiased, genome-wide pooled RNAi screen targeting over 17,000 genes identify that support orthopoxvirus infection. We used...
The Escherichia coli mispair-binding protein MutS forms dimers and tetramers in vitro, although the functional form vivo is under debate. Here we demonstrate that tetramer extended solution using small angle x-ray scattering crystal structure of C-terminal 34 amino acids containing tetramer-forming domain fused to maltose-binding (MBP). Wild-type MBP fusions formed could bind MutS-MutL-DNA complexes. In contrast, D835R R840E mutations predicted disrupt tetrameric interactions only allowed...