Bisphenol A researchers win Gabbay Award

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

Elledge wins Rosenstiel Award

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.


Rodal to Receive NIH New Innovator Award

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.

How yeast switch mating type and why we care

For grad students needing background on work in the Haber lab studying DNA recombination and repair, there are a couple new papers out to help you. A new review by Prof. Haber entitled Mating-type genes and MAT switching in Saccharomyces cerevisiae in Genetics provides a detailed introduction to literature. There’s a lot there… as Jim says in the Acknowledgements

The part of this work that derives from my own lab has been carried out for more than 30 years by an exceptional contingent of graduate students, postdoctoral fellows, technicians, and Brandeis University undergraduates […]

If methods papers are what you need instead, check out Sugawara & Haber (2012), Monitoring DNA Recombination Initiated by HO Endonuclease in Methods in Molecular Biology.

Children’s Leukemia Research Award to Fund Myosin Research

(from left to right) Director of Rosenstiel Center Jim Haber, Professor Carolyn Cohen, Dr. Jerry Brown, Anthony Pasqua, President of the Childrens Leukemia Research Association

On April 24, a Children’s Leukemia Research Association (CLRA) award was presented to Jerry Brown, a Senior Research Scientist who works with Carolyn Cohen at the Rosenstiel Basic Medical Sciences Research Center. The award will help fund research on structures of α-helical coiled-coils, in particular those from myosin implicated in certain leukemias. The α-helical coiled coil is a common dimerization motif in proteins and is implicated in many normal physiological as well as pathological processes. Many cases of acute myeloid leukemia involve the aberrant fusion of the transcription factor, CBFβ, to a long portion of the smooth muscle myosin rod, which is predicted from its amino acid sequence to form an α-helical coiled coil. A major aim of the proposed research is thus to crystallize and determine the atomic structures of the segment of the myosin rod nearest this fusion point, both in its normal unfused physiological state and when aberrantly fused to CBFβ. A related aim of the research is to understand how the conformations of α-helical coiled coils in general are affected by attached structures. Accomplishment of these aims may provide a structural basis for the rational design of drugs that can selectively disrupt the activity of the pathologically fused protein.

In addition to Dr. Brown and Professor Cohen, the award presentation was attended by their laboratory researchers Senthil Kumar, Ludmila Reshetnikova, and Elizabeth O’Neall-Hennessey, Rosenstiel Director James Haber, Brandeis Office of Research Administration Associate Director Patricia McDonough, Rosenstiel Department Operations Manager Anahid Keshgerian, CLRA President Anthony Pasqua, his daughter Susan (Pasqua) Bogue, a survivor of leukemia, and Nancy Golden and three of her children.   The award is named after another daughter of Nancy Golden, Amy Golden Uleis, who lost her battle with cancer at age 52 and was a graduate of Brandeis. The award presentation was accompanied by a photo-op and a small reception held at Rosenstiel.

Protein Flexing: A New Look at Transcription-Coupled DNA Repair

Alexandra M. Deaconescu, a research associate in the Rosenstiel Basic Medical Sciences Research Center and 2008-2010 Fellow of the Damon Runyon Cancer Research Foundation, together with Professor of Biochemistry and HHMI Investigator Nikolaus Grigorieff and collaborators in the Laboratory of Dr. Irina Artsimovitch at Ohio State University have just published a new study in PNAS, which delineates novel mechanistic details of transcription-coupled DNA repair.

In any cell, there is intense interplay between various DNA-based transactions, such as replication, transcription and DNA repair. More than twenty years ago, it was discovered that DNA lesions that cause stalling of RNA polymerase molecules elicit a form of preferential nucleotide excision repair (NER) that exists in both eubacteria and eukaryotes, and specifically targets the transcribed DNA strand. Termed transcription-coupled DNA repair (TCR), the process is found to be carried out in bacteria by an ATPase called Mfd or TRCF (see Figure, right). In TCR, TRCF performs two functions: 1) it recognizes a damage-stalled RNA polymerase (RNAP), then dissociates it off the DNA using energy derived from ATP hydrolysis and 2) it recruits DNA repair enzymes via binding to the UvrA subunit of the Uvr(A)BC NER machinery [1].   The Uvr(A)BC machinery is one of the main players in bacterial DNA repair, and distinguishes itself from other DNA repair proteins by its ability to repair a remarkably diverse repertoire of lesions by utilizing a “cut and patch” mechanism, whereby an oligonucleotide containing the damage is excised and the gap later filled.

The cellular role of TRCFs extends beyond TCR. Because of their ability to forward translocate and dissociate stalled RNAPs (or  “backtracked” RNAPs that have slid backwards on the template) [2], TRCFs are also involved in transcription elongation regulation [3, 4], resolution of head-on collisions of the transcription apparatus with the DNA replication machinery [5], and antibiotic resistance [6, 7]. In humans, the effects of impaired TCR are systemic and complex. Mutations in the transcription-repair coupling factor CSB lead to Cockayne Syndrome [8], a progeroid (accelerated-aging) disease characterized by severe developmental abnormalities and neurodegeneration, and whose etiology is currently poorly understood.

To elucidate the mechanism underpinning UvrA recruitment by TRCF, Deaconescu crystallized and solved the X-ray structure of a core UvrA-TRCF complex (Figure, left) demonstrating that UvrA binding involves unmasking of a conserved intramolecular surface within TRCF via a gating motion of the C-terminal domain (red in Figure above). Despite significant effort so far, Deaconescu is still trying to coax nucleotide-bound TRCF to form crystals suitable for X-ray diffraction. These would be highly informative because ATP is required for DNA binding, and its hydrolysis leads to TRCF translocation on dsDNA and ultimately release of RNAP off the damaged template.  Because diffracting crystals eluded her, and to further find out how ADP/ATP modulate the structure of TRCF, Deaconescu learned small-angle X-ray scattering techniques suitable for probing TRCF in solution in the absence and presence of nucleotides, thus circumventing the need for highly-ordered crystals. Then, the Brandeis team and their collaborators at Ohio State employed domain-locking disulfide engineering in conjunction with functional assays to gain a deeper understanding of what TRCF looks like during its catalytic cycle and upon binding to UvrA.  They find that the two main functions of TRCF (RNAP release and UvrA binding) can be uncoupled, suggesting that UvrA recruitment may only occur during/post RNAP release, and not upon RNAP binding as had been proposed earlier in the literature [9]. Furthermore, they show that the ternary elongation complex (consisting of RNAP, template and nascent RNA), but not naked DNA, significantly stimulates ATP hydrolysis by TRCF. Thus, bacterial TRCF operates in a manner reminiscent of that utilized by eukaryotic chromatin remodeling factors, and are preferentially stimulated by nucleosomes over naked DNA substrates.

Deaconescu previously “looked” at TCR using X-rays – as a graduate student she solved the first structure of an intact transcription-repair coupling factor from any organism using X-ray crystallography [10]. She now hopes to reconstitute the larger intermediates that form during TCR and bridge low- with high-resolution information using hybrid structural methods, particularly electron cryo-microscopy, and ultimately formulate a cogent model of how TRCFs operate in cells.

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