Key Discoveries

Catalyzing discovery in mechanistic biomedicine

Just as the groundbreaking work on CRISPR/Cas9 of former Max Perutz Labs scientist Emmanuelle Charpentier paved the way to genome editing, we strive to answer fundamental questions in biology with the potential to catalyze discovery in mechanistic biomedicine. Read some of the research highlights from the last 10 years of the Max Perutz Labs.

Key Discovery

CRISPR/Cas9 - how gene scissors work

Investigation of the mechanism of the CRISPR/Cas9 bacterial defense system has revolutionized biology, triggering applications in gene editing for basic and applied research in every organism imaginable. The basis for the revolutionary application of the CRISPR-Cas9 system was developed by Emmanuelle Charpentier at the Max Perutz Labs, whose work was published in Nature and Science.

Key Discovery

Meioisis: Mind the gap

To initiate the exchange of genetic material during meiotic recombination, cells introduce double strand breaks into chromosomes with an enzyme called Spo11, which cuts the DNA. Reporting in Nature, the team of Franz Klein has discovered that approximately 20% of initiation events are actually closely positioned pairs of DSBs. The scientists mapped the resulting fragments with single nucleotide precision across the yeast genome. This precision led to the discovery that Spo11 preferentially cleaves DNA at sites of topological stress. Intriguingly, double DSBs often correspond to promoter regions. While clearly a risk to genome integrity, the creation of gaps in chromosomes may represent an evolutionary mechanism by which to reshuffle genetic control elements.

Key Discovery

Autophagy: the beginning of the end

Autophagy ensures cellular health by removing harmful material from the cytoplasm. Defects in autophagy are suspected to be involved in several human diseases. During autophagy damaged or surplus material is sequestered by double membrane vesicles, called autophagosomes, which form de novo around the cargo. The factors involved in autophagosome formation are known, but how they cooperate to initiate the formation of these membranes has so far been enigmatic. In a study published in Science, the Martens lab shows how vesicles loaded with the protein Atg9 form seeds on which the autophagy machinery assembles to form the autophagosome.

Key Discovery

Touched by an ANGEL

RNA molecules are frequently modified with a terminal 2’,3’-cyclic phosphate group when processed in the cell. This modification influences the stability of RNA molecules and is important for pre-tRNA splicing, the unfolded protein response and the ribosome quality control (RQC) pathway. During investigations into how this modification is carried out in the cell, Javier Martinez’ group discovered a reaction that removes RNA cyclic phosphate groups in human cells. This activity was previously known only in bacteria and viruses. The enzyme catalyzing this reaction in human cells has, until now, remained enigmatic. Reporting in Science, the researchers identified an enzyme predicted to have deadenylase activity, ANGEL2, as a 2’,3’ cyclic phosphatase. The role of ANGEL2 in pre-tRNA processing and mRNA splicing during the unfolded protein response has exciting implications for the pathology of neurodegenerative diseases.

Key Discovery

Liquid enzymes regulate genes

Genetic information is tightly packed in chromatin, a material consisting of DNA strands weaved around histone proteins. Enzymes that modify histones by adding or removing specific chemical marks, alter the chromatin structure and thereby the activity of a gene. A key question in biology is how these enzymes are targeted to a specific gene to turn it on or off. Reporting exciting new findings in Nature, Alwin Köhler’s group found that one of these genetic switches behaves like a liquid. In the nucleus the protein Lge1 forms liquid droplets that act as a scaffold for Bre1, a histone-modifying enzyme that is sequestered on the surface of the liquid droplets. When dispersed, Lge1 quickly fuses together like oil droplets in water. This phenomenon, known as liquid-liquid phase separation, creates molecular crucibles where the necessary enzymes for gene regulation are condensed.

Key Discovery

A forgotten world gets a new facelift

Our genetic material is safeguarded by not one, but two membranes surrounding the cell nucleus. Communication between the cytoplasm and the nucleus is gated by nuclear pore complexes, which facilitate the regulated transport of molecules in and out. While the outer nuclear membrane has long been known to be metabolically active and is contiguous with the endoplasmic reticulum, the inner nuclear membrane has been regarded as a backwater of the endomembrane system. However, Max Perutz Labs scientist Alwin Köhler and his student Anete Romanauska now seek to overturn this notion. Köhler and his team have observed that the inner nuclear membrane is in fact metabolically active and have elucidated the genetic circuit for the synthesis of nuclear lipid droplets. The work, published in Cell, has implications for fat storage, gene transcription, and understanding human diseases such as congenital lipodystrophy.

Key Discovery

Timing is of the essence

Important biological processes, including feeding and reproduction, rely on accurate timing. Many organisms therefore possess internal clocks that enable them to coordinate their activities with the environment. Adaptation of the organism’s clock, or clocks, is key to survival. A team of Max Perutz Labs scientists, led by Kristin Teßmar-Raible, has identified genes relevant for this adaptation. Intriguingly, a signaling protein that is highly abundant in the brain, calcium/calmodulin-dependent kinase, appears to be the main effector of this adaptation. The results of the study, published in the journal Nature, offer a glimpse into potential molecular candidates for calibrating an organism’s internal clock.

Key Discovery

Gateways to the genome: nuclear pore complexes control gene transcription

Gene transcription is a highly dynamic process and correct export of messenger RNAs is key to the synthesis of the correct arsenal of proteins in the cytoplasm that the cell needs. Nuclear pore complexes have long been known to be the key transport routes for molecules in and out of the nucleus, but their role in gene transcription has been somewhat enigmatic. Max Perutz Labs scientist Alwin Köhler and a team of international collaborators now show that nuclear pore complexes make use of adaptor proteins to link actively transcribed regions of the genome to their export from the nucleus and translation in the cytosol. The work, published in Cell, provides the first mechanistic insight into how nuclear pore complexes communicate directly with the transcription machinery.

Key Discovery

Dropping anchor in the Z-disc

Most animals require muscles to feed, flee, or fight. Force generation during skeletal muscle contraction requires that actin filaments are firmly anchored in a structure called the Z-disc, an essential component of the sarcomere, which is the repeating building block of muscle fibres. An essential and major component of the Z-disc, α-actinin, is responsible for cross-linking actin filaments as well as anchoring the protein Titin, which controls sarcomere length. Mutations in α-actinin cause muscular dystrophies and cardiomyopathies. In work published in Cell, scientists at the Max Perutz Labs, led by Kristina Djinovic, have determined the three-dimensional structure of α-actinin, shedding new light on its regulation.

Key Discovery

Remodeling the bacterial ribosome in response to stress

To survive, bacteria must adapt to changing and often stressful environments. Adaptation strategies often center on changes in gene expression, which enable the bacteria to cope with the new environment. In work published in Cell, Isabella Moll and her team at the Max Perutz Labs show that the stress-induced endoribonuclease, MazF, selectively cleaves both a subset of mRNAs and the 16S rRNA in the decoding center of the 30S subunit of the ribosome. These modified ribosomes selectively translate the leaderless mRNAs produced by MazF and thereby tune the expression of genes required for stress adaptation.

Key Discovery

Mapping the meiotic recombination machinery

Phenotypic diversity in sexually reproducing organisms arises from the exchange of genetic material during the formation of gametes, or germ cells. In a process called meiotic recombination, the paternal and maternal chromosomes replicate, pair, and exchange parts of their DNA by forming double-strand breaks, which are later repaired. The organization of the double-strand break machinery that carries out this essential process has long been a mystery. Franz Klein and his team at the Max Perutz Labs show, in work published in Cell, that rather than visiting recombination hotspots, the DNA break machinery lurks at the chromosome axis to break DNA-sequences that come within reach.