Tenure-track positions in Biology (application deadline Oct 15)

The Biology Department at Brandeis University invites applications for up to two full-time, tenure-track appointments, beginning Fall 2016, from individuals who are conducting innovative research in the broad areas of molecular and cellular biology. Junior and more senior investigators will be considered, but preference will be given to hiring at the Assistant Professor level. Areas of interest range across molecular genetics, genomics and cell biology, including topics such as RNA biology, cytoskeleton, intracellular transport, development, signal transduction, transcriptional and post-transcriptional regulation, membrane biology, and epigenetics.

The research environment at Brandeis is highly collaborative, and we seek colleagues who will complement and extend existing strengths. Brandeis offers world-class research in the setting of a small liberal-arts university. Brandeis is located 7 miles from Boston, and is part of the vibrant research community of the greater Boston area.

Brandeis recognizes that diversity in its student body, staff and faculty is important to its primary mission of providing a quality education. The search committee is therefore particularly interested in candidates who, through their research, teaching and/or service experiences, will increase Brandeis’ reputation for academic excellence and better prepare its students for a pluralistic society.

To apply, please provide the following: a cover letter, a curriculum vitae, a summary of your research accomplishments to date, including a statement of your goals for future independent research (3-page limit), up to three publications, and at least three letters of reference. Applications will be accepted only through AcademicJobsOnline at https://academicjobsonline.org/ajo/jobs/6064.

First consideration will be given to applications received by October 15, 2015. Following an initial evaluation by the search committee, finalists will be invited to visit the campus to discuss their research and to meet with faculty and students/postdocs. Additional inquiries may be directed to Leslie Griffith or to Paul Garrity.

Brandeis University is an equal opportunity employer, committed to supporting a culturally diverse intellectual community. Applications are particularly encouraged from applicants of groups underrepresented in the sciences.

Patching Up Broken Chromosomes

Olga Tsaponina and James Haber’s recent paper “Frequent Interchromosomal Template Switches during Gene Conversion in S. cerevisiae” was published online by Molecular Cell on July 24, 2014.

by James Haber

“The process of copying DNA every time our cells divide is exceptionally accurate, but in copying 6,000,000,000 base pairs of the genome mistakes do occur, including both mutations and the formation of chromosome breaks. These breaks must be repaired to maintain the integrity of our chromosomes.  In our recent paper we have demonstrated that the mechanism of patching up a broken chromosome is associated with a surprisingly high level of alterations of the sequence.  Many of these changes result from “slippage” of the DNA polymerases copying the DNA during the repair process; for example in copying a sequence of 4 Gs, the polymerase occasionally jumps over one, to lose a base from the sequence (a frameshift mutation).

graphical_abstract_350In this paper we focused on more dramatic slippage events in which the copying machinery jumped from one chromosome to a related but divergent sequence on another chromosome and then jumped back, creating a chimeric sequence.  These interchromosomal template switches (ICTS) occur at a low rate when the distant sequence is only 71% identical, but if we make that segment 100% identical we could find such jumps 10,000 times more frequently, in about 1 in 300 events.  This result reveals how unstable the copying machinery in DNA repair is compared to normal DNA replication. This was very surprising and provides an explanation for many complex rearrangements associated with cancers.  In carrying out this work we identified the first protein that is needed to permit these frequent jumps: a chromatin remodeling enzyme known as Rdh54 that previously did not have a well-defined role in DNA repair in somatic cells.

Finally, we learned a new role for the proteins that survey the genome for mismatched bases that arise during replication and found that one of these proteins, Msh6, is required to specify which strand of DNA containing a mismatch is the “good one” that should be used as the template to correct the mismatch.

This work was supported by the National Institutes of Health General Medical Institute”.

A Cellular Rocket Launcher links Actin, Microtubules, and Cancer

Cells contain thousands of protein “micromachines” performing a bewildering number of chemical reactions every second. The challenge for biologists in the 21st century is to integrate information about multiple – or even all – proteins into holistic models for the entire cell. This is a daunting task. The addition of any new component to a system can alter the behavior of the components already there. This phenomenon is especially familiar to biologists studying the cytoskeleton, a complex system of protein filaments that provide the force for cell division and migration, among other things. The building blocks of the cytoskeleton are simple proteins called tubulin and actin that assemble into a remarkable variety of shapes depending on context. While the basic chemistry of this assembly process has been understood in purified systems for decades, how it happens in cells is not well understood. For example, growth of actin filaments is a two-step process: nucleation, or the formation of a new filament, and elongation, or the extension of that existing filament. Both steps happen just fine when actin is present in pure form in a test tube. In cells, however, proteins called profilin and capping protein block these two steps, respectively. Nucleation and elongation can only occur because other proteins overcome these blocks. Thus, a faithful experimental system to study actin assembly as it would occur in a living cell requires – at a minimum – five purified proteins.

One technological advance of great importance is the ability to literally see single molecules (in this case proteins) using advanced fluorescence imaging. In such an experimental system, many details can be captured. In a recent publication in Science, Dr. Dennis Breitsprecher and colleagues in the Goode and Gelles labs, undertook this challenge and directly visualized the effects of key regulatory proteins helping actin proteins nucleate and grow into filaments in the presence of both profilin and capping protein. A previous study from the Goode lab had shown that two proteins, called APC and mDia1, together stimulate the growth of actin into filaments (Okada et al, 2010). In the present study, Breitsprecher and colleagues examined the mechanism by which APC and mDia1 overcome the profilin and capping protein-imposed blocks. To do this, they ‘tagged’ actin, APC and mDia1 with three different fluorescent dyes, each of a different color, and then filmed these molecules (using triple-color TIRF microscopy) in the act of building an actin filament to learn precisely what they are doing.

The authors began by imaging APC and actin (2 colors) at the same time. APC formed discrete spots on the microscope slide, and growing actin filaments emerged from them, suggesting than APC nucleates actin filament formation. As the filament emerged from the APC spot, APC stayed where it was: remaining stably associated at the site of nucleation. Next, the authors added dye-labeled mDia1 to the system, and observed mDia1 molecules staying attached to and ‘riding’ the fast-growing end of actin filament, while protecting it from capping protein.

The most remarkable result came when they visualized all three labeled molecules together (actin, APC, and mDia1). What they saw was that APC and mDia1 first come together in a stable complex even before actin arrives. Then APC recruits multiple actin subunits to initiate the nucleation of a filament. This complex was resistant to the blocks imposed by both profilin and capping protein. As the filament grew from the APC-mDia1 spot, mDia1 separated from APC and stayed bound to the growing end of the filament – protecting it from capping protein while it grows. Thus, even though APC and mDia1 have different activities, participating in different stages of the growth of a filament, they associate together before actin even arrives, likely so that once the actin filament is born, it is immediately protected from capping protein. This mechanism has been compared to a rocket launcher: APC is the launch pad for an actin filament, which is then propelled forward by mDia1.

Rocket launcher images and cartoon

Rocket launcher mechanism for APC and mDia1 nucleation. Left: Microscopic image of a growing actin filament. APC stays put while mDia1 remains associated with the fast growing end. Right: Model for the rocket launcher mechanism.

The new study provides great detail of the system: for example, the number of APC subunits required to nucleate actin filaments was determined, and the growth rate of actin filaments in the presence and absence of all the other components was measured. Ultimately, all of these data will be required to put together a detailed model of how actin filaments grow inside of real cells: details that would be difficult or impossible to obtain without employing single molecule analysis.

For the future, the authors have set their sights on even more challenging experiments aimed at elucidating the mysterious link between tubulin and actin fibers. APC and mDia1 are implicated in this linkage in living cells, but almost nothing is known about how they physically link and/or communicate information between the two systems. Since APC is mutated in some 80% of colon cancer tumors, understanding its multiple roles is of clinical as well as intellectual importance. This will be an exciting, if challenging, endeavor for the future.

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.

New course in Cell Biology

The Department of Biology will offer a new course in Advanced Cell Biology (BIOL 100b) in Spring semester, 2012. The course is scheduled for Block D (MWTh 11:00-11:50a) and will be taught by Assistant Professor of Biology Satoshi Yoshida.

Yeast cytoskeletonThis is an advanced course on mechanisms of cellular functions, open to graduate students and advanced undergraduates with a strong interest in cell biology.

The class will use both textbooks and original literature,  and will cover broad topics in the field of cell biology. It will discuss why and how misregulation of cell function leads to diseases such as cancer and ageing. The goal of the course is not to simply provide a broad knowledge of cell biology, but also to learn how experiments were designed to test specific hypothesis and to learn how scientists interpret the data to make a model.

Who pulls the strings in actin cable assembly?

When large structures are built inside of cells, how are their dimensions determined? Are cues received that tell the structure to keep growing, or to slow down, or to stop growing altogether? A recent study published in Developmental Cell by a team led by Molecular and Cell Biology PhD student Melissa Chesarone-Cataldo and Professor of Biology Bruce Goode begins to address these questions by focusing on cytoskeletal structures called yeast actin cables.

Actin cables serve as essential railways for myosin-dependent transport of vesicles, organelles and other cargo, required for yeast cells to grow asymmetrically and produce a daughter cell. Cables are assembled at one end of the mother cell and run the length of the entire cell, but no longer, or else they would hit the back of the cell, buckle and misdirect transport. So how does an actin cable know how long to grow? How are other properties of the cable, such as its thickness and mechanical rigidity determined, and how important are these properties for cable function in vivo?

Actin cables are assembled at the bud neck by the formin protein Bnr1, and rapidly extend into the mother cell at a rate of 0.5-1 µm/s. At this speed, the tip of the actin cable reaches the back end of the cell in about 5-10 seconds. Each cable consists of many shorter overlapping pieces (individual actin filaments) that are stitched or cross-linked together to form a single cable, and cables continuously stream out of the bud neck due to the robust actin assembly activity of Bnr1. Chesarone-Cataldo et al. asked the question, “what mechanism prevents the cables from colliding with the back of the cell and overgrowing?” In doing so, they identified a novel actin cable ‘length sensing’ feedback loop, dependent on the myosin-passenger protein Smy1.

Using live-cell imaging, they showed that Smy1 molecules are transported by myosin from the mother cell to the bud neck, where they pause to interact with the formin Bnr1. Purified Smy1 attenuated Bnr1 activity by slowing down the rate of actin filament elongation. When the SMY1 gene was deleted, cables grew too long, hit the rear of the cell and buckled (see image, right). In addition, the mutant cables abnormally fluctuated in thickness and were kinked, impairing transport of myosin and its cargoes.

The authors propose that a negative feedback loop controls actin cable length. In their model, the cargo (Smy1 in this case) communicates with the machinery that is making the cable (the formin Bnr1), as a means of sensing ‘railway’ length. The longer the railway grows, the more passengers it picks up, and the more transient inhibitory pulses the formin receives. As such, longer cables are selectively attenuated, while shorter cables are allowed to grow rapidly. This negative feedback loop allows yeast cells to tailor actin cable length to the dimensions of the cell and to the needs of its myosin-based transport system.

Current work in the Goode lab is aimed at testing many of the mechanistic predictions of the model above and understanding how Smy1 functions in coordination with other known regulators of Bnr1, all simultaneously present in a cell, to produce actin cables with proper architecture and function. In addition, experiments are underway to find out whether related mechanisms are used to control formins in mammalian cells and to understand the physiological consequences of disrupting those mechanisms.

Chesarone-Cataldo M, Guérin C, Yu JH, Wedlich-Söldner R, Blanchoin L, Goode BL. The Myosin passenger protein Smy1 controls actin cable structure and dynamics by acting as a formin damper. Dev Cell. 2011 Aug 16;21(2):217-30.

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