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A "Goldilocks Zone" for Recruiting BET Proteins with Bromodomain-1-Selective Ligands.
ACS Chem Biol
November 2024
Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States.
Synthetic genome readers/regulators (SynGRs) are bifunctional molecules that are rationally designed to bind specific genomic sequences and engage cellular machinery that regulates the expression of targeted genes. The prototypical SynGR1 targets GAA trinucleotide repeats and recruits the BET family of transcriptional regulatory proteins via a flexibly tethered ligand, JQ1. This pan-BET ligand binds both tandem bromodomains of BET proteins (BD1 and BD2).
View Article and Find Full Text PDFSMARCD1 is a "Goldilocks" metastasis modifier.
bioRxiv
January 2024
Laboratory of Cancer Biology and Genetics, Metastasis Susceptibility Section, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, United States of America.
Breast cancer is the most frequently diagnosed cancer worldwide, constituting around 15% of all diagnosed cancers in 2023. The predominant cause of breast cancer-related mortality is metastasis to distant essential organs, and a lack of metastasis-targeted therapies perpetuates dismal outcomes for late-stage patients. However, through our use of meiotic genetics to study inherited transcriptional network regulation, we have identified a new class of "Goldilocks" genes that are promising candidates for the development of metastasis-targeted therapeutics.
View Article and Find Full Text PDFTelomere length and cancer risk: finding Goldilocks.
Biogerontology
April 2024
Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Drive, 6E456, Bethesda, MD, 20892-6772, USA.
Telomeres are the nucleoprotein complex at chromosome ends essential in genomic stability. Baseline telomere length (TL) is determined by rare and common germline genetic variants but shortens with age and is susceptible to certain environmental exposures. Cellular senescence or apoptosis are normally triggered when telomeres reach a critically short length, but cancer cells overcome these protective mechanisms and continue to divide despite chromosomal instability.
View Article and Find Full Text PDFSPOP targets the immune transcription factor IRF1 for proteasomal degradation.
Elife
August 2023
Department of Microbiology, Immunobiology and Genetics, Max Perutz Labs, University of Vienna, Vienna, Austria.
Adaptation of the functional proteome is essential to counter pathogens during infection, yet precisely timed degradation of these response proteins after pathogen clearance is likewise key to preventing autoimmunity. Interferon regulatory factor 1 (IRF1) plays an essential role as a transcription factor in driving the expression of immune response genes during infection. The striking difference in functional output with other IRFs is that IRF1 also drives the expression of various cell cycle inhibiting factors, making it an important tumor suppressor.
View Article and Find Full Text PDFPrioritized polycystic kidney disease drug targets and repurposing candidates from pre-cystic and cystic mouse Pkd2 model gene expression reversion.
Mol Med
May 2023
The Department of Cell, Developmental and Integrative Biology, Heersink School of Medicine, The University of Alabama at Birmingham, Birmingham, AL, USA.
Background: Autosomal dominant polycystic kidney disease (ADPKD) is one of the most prevalent monogenic human diseases. It is mostly caused by pathogenic variants in PKD1 or PKD2 genes that encode interacting transmembrane proteins polycystin-1 (PC1) and polycystin-2 (PC2). Among many pathogenic processes described in ADPKD, those associated with cAMP signaling, inflammation, and metabolic reprogramming appear to regulate the disease manifestations.
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