Geneticist Frederick Alt ’71 will be awarded the 44th Rosenstiel Award for Distinguished Work in Biomedical Science by Brandeis University for his pioneering research exploring the mechanisms of genomic instability and its implications for the immune system and cancer cells. Alt is the second alumnus to win the Rosenstiel Award; the first, Rod McKinnon ’78, won the Rosenstiel in 1999 and went onto win the Nobel Prize in 2003. Learn more on Brandeis Now …
On July 14, 2014, PLOS ONE published a paper from the Haber and Kondev labs. The paper, Effect of chromosome tethering on nuclear organization in yeast, was authored by Baris Avsaroglu, Gabriel Bronk, Susannah Gordon-Messer, Jungoh Ham, Debra A. Bressan, James E. Haber, and Jane Kondev.
by Baris Avsaroglu
Chromosomes are folded into the cell nucleus in a non-random fashion. In yeast cells the Rabl model is used to describe the folded state of interphase chromosomes in terms of tethering interactions of the centromeres and the telomeres with the nuclear periphery. By combining theory and experiments, we assess the importance of chromosome tethering in determining the spatial location of genes within the interphase yeast nucleus. Using a well-established polymer model of yeast chromosomes to compute the spatial distributions of several genetic loci, we demonstrate that telomere tethering strongly affects the positioning of genes within the first 10 kb of the telomere. Further increasing the distance of the gene from the telomere reduces the effect of the attachment at the nuclear envelope exponentially fast with a characteristic distance of 20 kb. We test these predictions experimentally using fluorescently labeled genetic loci on chromosome III in wild type and in two mutant yeast strains with altered tethering interactions. For all the cases examined we find good agreement between theory and experiment. This study provides a quantitative test of the polymer model of yeast chromosomes, which can be used to predict long-ranged interactions between genetic loci relevant in transcription regulation and DNA recombination.
Sorting and processing of the proteins that span cell membranes requires extensive membrane remodeling , including budding, tubulation, and fission. F-BAR domains form crescent-shaped dimers that bind to and deform membranes. Until now, it was thought that proteins containing these F-BAR domains induced membrane tubulation by assembling in highly ordered helical coats on lipid bilayers.
A new paper in Molecular Biology of the Cell from the Rodal lab (in collaboration with the Nicastro lab and the Sokolova Lab at Lomonosov Moscow State University) describes a novel membrane deforming activity for Nervous Wreck (Nwk), an F-BAR protein that regulates trafficking of transmembrane growth signal receptors at the Drosophila neuromuscular junction. The authors found that Nwk assembles into zig-zags on lipid monolayers, unlike the canonical F-BAR protein CIP4 which forms long filaments, even though the two proteins are predicted to be very structurally similar. Unlike other members of the F-BAR family that tubulate the membrane, Nwk can induce the formation of membrane ridges and scallops (see figure below). These deformations can lead to dramatic cellular remodeling in cooperation with the cytoskeleton (see figure above). The work done by the Rodal lab suggests that while basic self-assembly and membrane binding properties are likely conserved between F-BAR proteins, the higher-order organization of Nwk may account for differences in membrane remodeling and its specialized role in the cell.
Professor Jim Haber presented the following memorial tribute at Faculty Meeting on Nov 8, 2012:
Professor Emeritus Pieter Croissant Wensink passed away on October 2, 2012 in Wellesley, MA. Pieter was born in Washington, DC, in 1941, and grew up in Bethesda and Chevy Chase, MD. He attended Lawrence College in Appleton, WI, but like many young people in the 60s, dropped out. He ended up working in a laboratory at Johns Hopkins, where he discovered a passion for science. He never got his BA, but by taking night courses Pieter got himself accepted as a graduate student at Johns Hopkins, where he received his PhD in Biology in 1971, working with Don Brown, a pioneer in studying the regulation of gene expression in frogs. Pieter then went to Stanford, where he did post-doctoral work with David Hogness. At Stanford, Pieter got in on the ground floor of the new recombinant DNA technology. He published, with Hogness, a landmark paper entitled “A system for mapping DNA sequences in the chromosomes of Drosophila melanogaster” – the fruit fly.
In 1975 Pieter came to Brandeis as an Assistant Professor in the Rosenstiel Center and in the Department of Biochemistry, bringing to Boston the then-rare and prized knowledge of how to clone genes. I remember clearly in 1976 when an MIT professor, David Botstein, and his postdoc, Tom Petes, camped out at Brandeis for several weeks learning from Pieter how to clone yeast genes. Their collaboration resulted in another major paper “Isolation and analysis of recombinant DNA molecules containing yeast DNA.” Soon thereafter Matthew Mesleson arrived from Harvard, to collaborate with Pieter on the “Sequence organization and transcription at two heat-shock loci in Drosophila.” All of these papers were pioneering works.
Pieter also taught these “dark arts” to the people in my lab and launched us and others at Brandeis on the way to understanding the mysteries of chromosome architecture and gene regulation. In 1981 Pieter also wrote a book in collaboration with his Biochemistry colleague Bob Schleif: Practical Methods in Molecular Biology.
Pieter’s own work, carried out with a series of superb graduate students, focused on genes that encode the proteins that make up the yolk of Drosophila eggs. The study of these genes revealed the complicated way that yolk protein genes are turned on only in females and only in their ovaries. Many of Pieter’s students are now Professors in their own right at major universities around the country.
In the early 1990s Pieter was diagnosed with a benign brain tumor – a meningioma – that required two surgeries to extirpate. Probably his tumor was the result of the now-impossible-to-believe treatment of a ringworm infection with X-rays when he was about 2 years old. The second operation left him unable to concentrate as he had, and Pieter, sadly, decided that he could no longer run his lab or give the clear lectures had had been offering. So he left Brandeis as an emeritus Professor with a medical disability. Pieter was remarkably calm and accepting about his situation. He decided to pursue a long-deferred passion to paint, and some years ago he earned his BFA with distinction in painting from the Massachuetts College of Art. Altogether, Pieter had 5 operations on the cancers that led to his death.
Pieter’s greatest joy in life was his family. He was married to Dorothy E. (Perry) for 43 years and was the devoted father of Tom, Alan and Joe (who recently earned his PhD in English from Brandeis).
Most of you never met Pieter, so I thought it would be good to see Pieter and some of his colleagues as we looked in the late1970s (Pieter, Michael Rosbash, Marion Nestle (now oft-interviewed nutritionist at NYU), myself, and David DeRosier). And to see two of his paintings. He was a fine man.
Bisphenol A (BPA) has been used in the synthesis of polycarbonate plastics over the years. BPA is also a powerful estrogen analog. Three researchers, Patricia Hunt (Washington State Univ.), Ana Soto (Tufts) and Carlos Sonnenschein (Tufts), will today be awarded the 2012 Jacob Heskel Gabbay Award for their work identifying the cellular and developmental effects of BPA exposure. The three will lecture today, Oct. 22, at 3:30 pm in Rapaporte Treasure Hall, Goldfarb Library.
see also story at BrandeisNOW
Professor Stephen J. Elledge of the Harvard Medical School and the Howard Hughes Medical Institute has been awarded the 42nd Rosenstiel Award For Distinguished Work in Basic Medical Science for “elucidating how eukaryotic cells sense and respond to DNA damage”. He identified key DNA damage response genes both in yeast and mammalian cells, showed how the pathway is activated by DNA lesions, and made key contributions to defining the cascade of phosphorylation events that enforces cell cycle arrest and controls DNA repair. Dr. Elledge’s work is also marked by the development of powerful research tools to uncover the network of genes involved in sensing and repairing DNA damage. His pioneering work laid the foundation for our current understanding of how failures in DNA damage sensing relate to the medically important field of genome instability.
The Rosenstiel Award consists of a cash prize and a medal, to be awarded at a dinner at Brandeis on March 14, 2013.
- For a recent review, see The DNA Damage Response: Making it safe to play with knives
- see story at BrandeisNOW
The NIH recently announced that Assistant Professor of Biology Avital Rodal will be a recipient of the 2012 NIH Directors New Innovator Award. The award allows new, exceptionally creative and ambitious investigators to begin high impact research projects. Granted to early stage investigators, candidates are eligible for the award for up to ten years after the completion of their PhD or MD. The award emphasizes bold, new approaches, which have the potential to spur large scientific steps forward. This year’s award was made to fifty-one researchers, and provides each with 1.5 million dollars of direct research funding over five years.
The Rodal lab studies the mechanisms of membrane deformation and endosomal traffic in neurons as they relate to growth signaling and disease. Membrane deformation by a core set of conserved protein complexes leads to the creation of tubules and vesicles from the plasma membrane and internal compartments. Endocytic vesicles contain, among other cargoes, activated growth factors and receptors, which traffic to the neuronal cell body to drive transcriptional responses (see movie). These growth cues somehow coordinate with neuronal activity to dramatically alter the morphology of the neuron, and disruptions to both endocytic pathways and neuronal activity have been implicated in neurodegenerative diseases such as amyotrophic lateral sclerosis and Alzheimer’s disease.
Dr. Rodal hopes to determine how neuronal activity affects the in vivo function and biochemical composition of the membrane trafficking machinery, by examining the transport of fluorescently labeled growth factor receptors in chronically or acutely activated neurons at the Drosophila neuromuscular junction (NMJ). Her group will combine these live imaging studies with a proteomic analysis of endocytic machinery purified from hyper-activated and under-activated neurons. By investigating the interplay between neuronal activity, membrane deformation, and receptor localization in live animal NMJs, she hopes to gain a better understanding of the strategies that healthy neurons employ to regulate membrane trafficking events, and provide new insight into specific points of failure in neurodegenerative disease.
- see also story at Brandeis NOW