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Biochemistry and Molecular Biology Department

Research Highlights

Check out some of the recent discoveries from our labs

Neuron, 2023

Wang Lab Research

colorful microscopy image of cells, with many dense red dots and more diffuse blobs of blue

DNA-initiated epigenetic cascades driven by C9orf72 hexanucleotide repeat, Liu et al, 2023, Neuron

Jiou Wang’s lab has shown that a repeat expansion mutation linked to neurodegeneration may cause disease through its effects triggered directly by the DNA, independent of mutation’s downstream effects on RNA and protein that have been demonstrated by his lab and others.

The C9orf72 gene normally has two to ten “GGGGCC” repeats in a non-coding region, but the hexanucleotide repeat expansion mutations have hundreds to thousands. Led by postdoctoral fellow Yang Liu, PhD, the lab showed that a DNA-binding protein called DAXX preferentially binds to this much longer repeat region and accumulates in the cell.

The accumulation of DAXX has a cascade of pathologic effects: it triggers a liquid-liquid phase separation that drives chromatin structure and epigenetic modifications changes, suppresses the normal stress-dependent induction of C9orf72, and influences global gene expression. These findings may open up new prevention or treatment strategies for neurodegenerative diseases, and in fact the researchers found that reducing DAXX or rebalancing the epigenetic modifications reduced the sensitivity of patient neurons to stress.

For more details about the research, check out the paper at Neuron.

Journal of Biological Chemistry, 2023

Matunis Lab Research

Microscopy image of three cells: mottled blue oval centers surrounded by red strands stretching to fill the cell, speckled with tiny green dots, on a black background

Analysis of a degron-containing reporter protein GFP-CL1 reveals a role for SUMO1 in cytosolic protein quality control, Wang et al, 2023, Journal of Biological Chemistry

The Matunis lab has uncovered a new role for small ubiquitin-related modifiers, or SUMO, in protein quality control, the surveillance mechanisms that cells use to identify and degrade misfolded proteins – for the first time showing a role in PQC in the cytoplasm, rather than nucleus. The accumulation of misfolded proteins can cause proteotoxic stress that can damage cells and is associated with multiple human diseases, including neurodegeneration, and these findings may provide insights into the role of sumolyation in those diseases.

Led by BMB PhD student Wei Wang, the researchers showed that in the yeast Saccharomyces cerevisiae and in humans, a SUMO protein is required for the timely turnover of a PQC reporter protein containing the CL1 degron, a short degradation signal that can misfold and trigger rapid degradation of the protein. SUMO only affected the turnover in the cytoplasm, not the nucleus. Experiments examining different aspects of the CL1 degron response pathway showed that SUMO’s role is upstream of the ubiquitylation and proteasome activity steps, and suggest that it promotes degradation by maintaining the solubility of the reporter proteins, but more research is needed to fully understand the mechanisms involved.

For more details check out the paper at the Journal of Biological Chemistry.

Nature Communications, 2022

Wang Lab Research

Hundreds of fluorescent blue, pink, green and red dots smeared on black background

Intracellular energy controls dynamics of stress-induced ribonucleoprotein granules, Wang et al, 2022, Nature Communications

Jiou Wang’s lab studies fundamental mechanisms of neurodegenerative diseases, which are often associated with cellular stress and disrupted energy metabolism. They have discovered a unique type of ribonucleoprotein granule that can be formed under energy deficiency stress conditions. 

 Stress granules, or SGs, comprising condensed proteins and RNAs, are a type of membraneless organelle induced by certain stressors. Researchers studying cells with disrupted energy metabolism found a new type of stress-induced granule: energy deficiency-induced stress granules. These eSGs have a distinct protein composition and higher RNA contents, suggestive of different functions. They also assemble differently, independent of translation factor eIF2α phosphorylation that is a hallmark of conventional SGs.

Neurons derived from patients with a major form of motor neuron degenerative disease, which have pre-existing metabolic disruptions, had abnormal eSG formation, suggesting its relevance to the disease processes. Full details, including more about eSG features and assembly, are in Intracellular energy controls dynamics of stress-induced ribonucleoprotein granules at Nature Communications.

Biochemistry, 2022

Kavran Lab Research

A cartoon hippopotamus next to cartoon renderings of proteins: a blue MST1/2 with an attached pink MOB1a; next to and connected by lines are a green RASSFs and orange SAV1

Kinetic Regulation of the Mammalian Sterile 20-like Kinase 2 (MST2), Koehler, Tran, et al, 2022, Biochemistry.

Jennifer Kavran’s lab studies HIPPO: not the fierce but adorable semi-aquatic mammal, but a signaling pathway with roles that include tumor suppression.

Led by PhD student TJ Koehler and then-postdoc Thao Tran, the lab studied kinetic regulation of key Hippo kinase MST2. Examining the activity of different versions of MST2 under different conditions, they showed that by far the largest driver of MST2 activity was if it was phosphorylated, regardless of which domains were present.

They revealed a novel role of the C-terminal SARAH domain: it dramatically increased activity in unphosphorylated proteins, but reduced it in phosphorylated proteins, with evidence suggesting that it disrupted interactions with ATP. They also found that some factors that affect MST 1/2 activity in cells, such as caspase cleavage, had little impact on this in vitro activity, suggesting that these factors influence non-kinetic aspects of the pathway in vivo, such as cellular localization.

Check out the paper in Biochemistry for all the details!