Alex’s life as a fly barista

Alex Dainis ’11 writes about her experiences in the Garrity lab studying the genetics of nociception in fruit flies in her story “My life as a fly barista” on the Life@Deis blog.

Update: see the later story on this blog about the Nature paper on which Alex is an author.

Bacterial phenomics

As a self-confessed prokaryotic chauvinist, I’m always on the lookout for new interesting papers aimed at understanding bacterial metabolism and regulation. A recent paper in Cell, entitled “Phenotypic Landscape of a Bacterial Cell” by a group of authors including Biology Professor Susan Lovett demonstrates the application of high-throughput screening to finding new bacterial phenotypes. Approximately 4000 E.coli mutant strains, representing deletions of individual non-essential genes, were plated on 324 different media representing a total of over 100 different stress conditions, and the growth followed by image analysis. Approximately half of the genes screened had one or more identifiable phenotypic repsonses. This approach allows the identification of genes that are conditionally essential, genes that are involved in multiple resistance, etc. This represents a new automated method for identifying phenotypes (hence “phenomics’) and understanding the roles of genes of as yet unidentified function in bacteria. The data set is publicly available at

Getting a Leg Up on Movement Disorders

Over 40 million people worldwide suffer from movement disorders, which are clinically defined as any type of affliction that affects the speed, fluency, ease, or quality of motion. The symptoms of these disorders can manifest in many different ways (the most common being tics, tremors, dystonia, and chorea), and treatment is still elusive for a large number of these often debilitating diseases.  The past several decades, however, have seen enormous advances in our understanding of the genes and proteins underlying these conditions, and what remains to be determined is the way in which these molecules interact with each other to produce either normal or pathological locomotor patterns.

Scaffolding proteins have recently become a point of interest in the field of movement disorders.  As their name implies, these proteins act as “scaffolds” to tether other proteins together, thus facilitating protein-protein interactions.  It has long been thought that scaffolding protein dysfunction could disrupt the formation of protein complexes critical for the production normal locomotion, but evidence for such conjectures has remained elusive.

in a recent article in the journal GENETICS, Dr. Leslie Griffith’s lab at Brandeis University published work implicating one such scaffolding protein of the MAGUK family, known as CASK-b, in locomotor pathology. Using the fruit fly Drosophila melanogaster as a model system, researchers in the lab combined recently-developed genetic tools with cutting-edge computer behavior analysis software to demonstrate that knocking out this protein produces a complex motor deficit (see figure below).  Furthermore, this deficit appears to stem from a loss of CASK-b in the central nervous system, suggesting it plays a role in higher-order regulation of motor output.  Interestingly, both the major locomotor control center of the insect brain (known as the ellipsoid body), as well as the motor neurons which the locomotor control center regulates, do not appear to require this protein to produce normal locomotor patterns.  This finding implies that a novel region or regions of the fly brain may be contributing to central locomotor control.  Understanding both the specific mechanism through which this protein acts, as well as the underlying circuitry responsible for this deficit, could contribute largely to the field of movement disorders as a whole.

Another surprising finding to come out of this study was the discovery of an additional mRNA transcript that arises from an alternative promoter in the CASK locus.  Although similar to CASK-b in many ways, this alternative protein is actually most homologous to another member of the same family in vertebrates, known as MPP1.  MPP1, like most of its MAGUK cousins, is also a scaffolding protein that plays a vital role in bringing various proteins together into signaling complexes, thus providing more opportunities for complex interactions to take place.  The Drosophila genome has many fewer MAGUK proteins than most mammalian genomes.  This finding implies that through utilization of alternative start sites that generate multiple proteins, the fly can still end up with a wide array of subcellular interactions.  It is this underlying diversity of molecular interactions that is thought to allow the fly to produce to a variety of unusually complex behaviors, such as courtship, aggression, flight, and in this case motor control.

Hello, Professor. What is Genetics?

Questions about this spring’s BIOL 22A Genetics course are answered in a short video.

Allis, Grunstein to receive 2011 Rosenstiel Award

The 2011 recipients of the Lewis S. Rosenstiel Award for Distinguished Work in Basic Medical Science are C. David Allis (Rockefeller Univ.) and Michael Grunstein (UCLA) for their discovery that histones and histone acetylation directly regulate transcription.  There will be lectures and an award ceremony at Brandeis University on April 14, 2011 at 3:30 pm in the Carl J. Shapiro Theater, Shapiro Campus Center

C. David Allis
(Tri-Institutional Professor, Joy and Jack Fishman Professor, Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University)

Beyond the Double Helix: Varying the ‘Histone Code’
Michael Grunstein
(Distinguished Professor , Department of Biological Chemistry , University of California, Los Angeles )
Towards histone function

A reception will follow in the Shapiro Science Center Atrium for all attendees of the talk, from roughly 5:30 until 7 pm.

For more information, see Brandeis NOW and the Rosenstiel Award website.

Phosphatases and DNA double strand break repair

When cells suffer DNA damage – as little as a single break in one chromosome – they respond by activating the DNA damage checkpoint, which prevents cells from entering mitosis until there is enough time to to repair the damage.  The principal biochemical events in the checkpoint pathway are the phosphorylations of protein kinases by other protein kinases and eventually the phosphorylation of other proteins that regulate mitosis.    When repair is complete, the checkpoint must be turned off.  Not surprisingly, the enzymes that turn off the checkpoint are phosphatases that can remove the phosphates added by the protein kinases.

The Haber lab has previously shown that, in budding yeast, a pair of PP2C phosphatases known as Ptc2 and Ptc3 were important in turning off a key protein kinase, Rad53.  A member of another phosphatase subgroup, the PP4 phosphatase Pph3, dephosphorylates a target of the checkpoint kinases, histone protein H2A.  There is one aspect that they didn’t understand at all: It seems that the intensity of the checkpoint signals must grow the longer it takes to repair DNA damage, because deletions of ptc2 and ptc3 or a deletion of pph3 prevented cells from turning off the damage signal when it took a long time – 6 hours – to repair the damage, but they had much less effect on different repair events that could complete in 3-4 hours or in less than 2 hours.  So they decided to see what would happen if they created a yeast strain lacking all three phosphatases (ptc2 ptc3 pph3), leading to a paper appearing this month in the journal Molecular and Cell Biology.

To their surprise, these cells had a new defect: they couldn’t complete the repair event itself, rather than simply being defective in resuming mitosis after repair was completed.  The mutants could not properly initiate the small amounts of DNA copying that are required for repair.  Again, the severity of the defect depends on the length of the delay it takes to initiate the repair event itself.  The figure (right) shows that the triple mutant is also much more sensitive to DNA damaging agents such as the anti-cancer drug camptothecin (CPT) and to methylmethansulfonate (MMS). These data show a complex connection between DNA damage signaling and the repair process itself, and reveal new roles for the phosphatases in DNA repair.  The work was carried out primarily by graduate student Jung-Ae Kim, now a postdoc at Rockefeller University, with help by another grad student, Wade Hicks, and by an undergraduate Sue Yen Tay, and postdoc Jin Li. The work was supported by a research and a graduate student training grant from the NIH.

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