Our lab studies DNA break repair and genetic recombination in bacteria (E. coli) and fission yeast (S. pombe) using both genetic and biochemical methods.  When their DNA is broken, cells must repair it or they die.  Successful repair often employs homologous recombination, the generation of new combinations of gene alleles that provide the diversity for evolution to proceed efficiently.  During sex cell formation (meiosis) DNA is programmed to be broken...
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One major focus of our research is to understand the role of selective protein destruction in eukaryotic biology and human diseases. Just like protein synthesis, protein degradation is tightly controlled in all eukaryotic organisms and is frequently involved in the regulation of diverse cellular functions. We are interested in dissecting how different cellular signals induce specific protein degradation in human cells, thereby, mediating various biological processes, such as cell cycle progression, tissue differentiation, stress response, and circadian rhythm...
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Gene Inversion Potentiates Bacterial Evolvability and Virulence

The research in Houra Merrikh’s lab is focused on bacterial DNA replication, repair, mutagenesis, and evolution. Our studies on DNA replication are focused on identifying the way cells handle the inevitable collisions between the replication and transcription machineries. We have found that these events increase mutagenesis in a gene-specific manner and increase the ability of bacteria to rapidly evolve. These discoveries have helped us identify important molecular mechanisms that allow bacteria to develop antibiotic resistance...
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Chimeric antigen receptor-modified (CAR)-T cells have demonstrated impressive results in the treatment of haematological malignancies. However, cytokine release syndrome (CRS) and neurotoxicity are common toxicities which are potentially life-threatening in severe cases. Risk factors for CRS and neurotoxicity identified so far include disease burden, lymphodepletion intensity and CAR-T cell dose administered. Risk-adapted dosing, with lower CAR-T cell doses administered to…
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BbvCI, a Type IIT restriction endonuclease, recognizes and cleaves the seven base pair sequence 5′-CCTCAGC-3′, generating 3-base, 5′-overhangs. BbvCI is composed of two protein subunits, each containing one catalytic site. Either site can be inactivated by mutation resulting in enzyme variants that nick DNA in a strand-specific manner. Here we demonstrate that the holoenzyme is labile, with the R1 subunit…
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This publication reports on the structural mechanism by methylated CpG motifs are maintained following DNA replication. Surprisingly, the DNA methylation reaction requires action by a ubiquitin E3 ligase, UHRF1. We show how a small domain in UHRF1 couples the recognition of a CpG site that requires methylation to the modification of histone H3 with ubiquitin, which in turn recruits the DNA methyltransferase, DNMT1. We show that known cancer-associated mutations in this domain of UHRF1 uncouple the recognition and modification reactions...
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Our recent work discovered stem cell differentiation as the primary block to oncogene-driven clonal expansion in skin epithelium. In doing so our study made several significant contributions. First, it established differentiation along with senescence and apoptosis as oncogene-driven tumor suppressive processes. Second, it provideed a detailed cellular and molecular mechanism for how skin may tolerate and therefore accumulate oncogenic lesions over time without showing any functional or morphological defects...
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Human and rodent brains are clearly different in terms of size and complexity.  Yet, how the constituent parts of rodent versus human brain differ is unclear. We provide evidence that the physiological properties of human and mouse supragranular pyramidal neurons differ substantially in part because of differences in the expression of an ion channel, the h-channel. Consequently, human and mouse supragranular pyramidal neurons integrate synaptic input differently.  For example, human neurons prefer synaptic input containing frequencies associated with learning and attention...
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Dormant Tumor Cells, Their Niches and the Influence of Immunity

Despite increased focus on the clinical relevance of dormant metastatic disease, our understanding of dormant niches, mechanisms underlying emergence from dormancy, and the immune system’s role in this phenomenon, remains in its infancy. Here, we discuss key work that has shaped our current understanding of these topics. Because tumour dormancy provides a unique therapeutic window to prevent metastatic disease, we…
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De Novo Design of a Non-Local β-Sheet Protein with High Stability and Accuracy

Natural proteins evolved over billions of years to solve biology’s most complex problems. But we face new and pressing challenges today. The goal of my lab at the UW Institute for Protein Design is to develop and apply methods for designing a whole new world of synthetic proteins to address 21st-century challenges in precision medicine, energy production, manufacturing, and more. We combine computer science and molecular biology to design novel proteins from first principles that can serve as medicines, vaccines, catalysts, biomaterials, sensors, and beyond...
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