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”.

Art Wingfield Festschrift – “Age, Hearing, and Speech Comprehension”

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On July 22nd, 70 colleagues, friends, and students gathered for a festschrift in honor of Art Wingfield, the Nancy Lurie Marks Professor of Neuroscience. The theme of the day was Age, Hearing, and Speech Comprehension, reflecting Art’s research interests.

Brandeis_072214_064In addition to a scientific program composed of talks centered on this topic, the day also featured former students, collaborators, and colleagues sharing stories about Art. These included Stefanie Kuchinsky (2003) who completed a senior honors project in Art’s lab, former postdoc Marianne Fallon, former students Cindy Lahar and Sarah Wayland, and colleagues from the Department of Psychology (Jim Lackner and Paul Dizio).

The day ended with the surprise announcement of the establishment of an annual travel award in Art’s name that will support a graduate student in psychology or neuroscience to travel to a scientific conference, and dinner in town. A great time was had by all!

More information, photos, and stories can be found at www.artwingfieldfest.com.

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Images: Heratch Photography

How regulatory sequences evolve in fruit flies

An IMP-Brandeis collaboration reveals the evolution of regulatory sequences in Drosophilids

By Yuliya Sytnikova and Nelson Lau

Enhancers are cis-regulatory DNA sequences that influence the promoters of genes, but identifying enhancers is not a straightforward process. Previously, the Stark lab developed a method for genome-wide enhancer detection called STARR-seq, (Arnold, Gerlach et al. 2013), that allowed them to identify thousands of enhancer sequences around the Drosophila melanogaster genome. In the most recent issue of Nature Genetics, a collaboration between the Stark lab of the IMP (Institute of Molecular Pathology) in Vienna, Austria, and the Lau lab at Brandeis University examines this hypothesis by studying the conservation of enhancer regulatory regions during Drosophilid fly evolution.

To ask if enhancers from D. melanogaster enhancers are also conserved in other Drosophila species in their sequences and locations, the Stark lab extended the STARR-Seq approach to D.yakuba and D.ananassae, which are separated from D.melanogaster by 11 and 40 million years ago, respectively (Arnold, Gerlach et al. 2014). Interestingly, this study also revealed hundreds of new sequences that gained enhancer function differentially between D.yakuba, D.ananassae, and D.melanogaster.

However, to test if these new sequences meaningfully direct different gene expression changes, the Lau lab conducted a targeted mRNA profiling experiment in purified endogenous follicle cells from D.yakuba and D.ananassae. The Stark lab had initiated the STARR-Seq analysis in an Ovarian Somatic Cell (OSC) line, which originated from the follicle cells of D.melanogaster, therefore the profiling of endogenous follicle cells from D.yakuba and D.ananassae was critical. The Lau lab achieved this using a methodology they developed for profiling Piwi-interacting RNAs from these cells (Matts, Synikova et al. 2013).

Figure 6: Evolution of enhancer activity in OSCs and gene expression in follicle cells in vivo.

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Arnold CD, Gerlach D, Spies D, Matts JA, Sytnikova YA, Pagani M, Lau NC, Stark A. Nat Genet. 2014 Jun 8. doi: 10.1038/ng.3009. [Epub ahead of print] Quantitative genome-wide enhancer activity maps for five Drosophila species show functional enhancer conservation and turnover during cis-regulatory evolution.

Matts JA, Sytnikova Y, Chirn GW, Igloi GL, Lau NC. Methods Mol Biol. 2014;1093:123-36. doi: 10.1007/978-1-62703-694-8_10. Small RNA library construction from minute biological samples.

 

“Age, Hearing, and Speech Comprehension”: A Festschrift for Art Wingfield

artWingfieldBlogA one-day event will be held on July 22, 2014 at the Shapiro Campus Center Theater to honor Art Wingfield, the Nancy Lurie Marks Professor of Neuroscience, for his 40+ years of research and teaching at Brandeis. During his time at Brandeis, Art has made contributions to the areas of speech comprehension, cognitive aging, memory, and aphasia and has mentored numerous PhD students, research assistants and postdocs. Art has inspired countless other students in his course on Human Neuropsychology.

Some of the speakers will include former lab members and prominent researchers in the field:

  • Mark Eckert, Department of Otolaryngology,
    Medical University of South Carolina
  • Murray Grossman, Department of Neurology,
    University of Pennsylvania
  • Stefanie Kuchinsky, Center for Advanced Study of Language,
    University of Maryland
  • Jonathan Peelle, Department of Otolaryngology, Washington University in St. Louis
  • Kathy Pichora-Fuller, Department of Psychology, University of Toronto Mississauga
  • Robert Remez , Department of Psychology, Columbia University
  • Bruce Schneider, Department of Psychology, University of Toronto Mississauga
  • Liz Stine-Morrow, Department of Educational Psychology and Beckman Institute, University of Illinois, Urbana-Champaign

For more information about this event can be found at www.artwingfieldfest.com/.

If you are interested in attending, please register at by July 5th.

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