Gio Biosco (P’98) gets NIH Pioneer Award

Molecular and Cell Biology alum Giovanni Bosco Giovanni Bosco Ph.D. ’98, currently Associate Professor of Genetics at Dartmouth, recently received a Pioneer Award from the NIH.

Gio Bosco is a die-hard chromatin regulation guy who became interested in whether long-term changes in DNA structure are involved in long-term behavioral plasticity. Gio did his PhD work in Jim Haber’s lab and provided some of the earliest and strongest evidence for a critical DNA repair mechanism called break-induced replication, which plays an essential role in maintaining the integrity of chromosome ends when the normal end-addition of DNA by telomerase is absent.

In his postdoctoral work, Giovanni turned from using yeast as a model system to Drosophila.  In the lab of Terry Orr-Weaver at MIT he focused his attention on the role of DNA replication in regulating gene amplifications and became interested in the importance of post-translational modifications (acetylations and phosphorylations) of the histone proteins that wrap the DNA into chromatin.

Approximately 7 years ago Gio started contemplating the question of how these post-translational histone modifications change during behavior and learning. He returned to his Brandeis roots to develop tools and approaches to address this problem. He received an NIH K18 grant to fund a sabbatical in Leslie Griffith’s lab in 2010. He and his behavior group have remained connected to Brandeis since then through frequent joint group meeting visits.

We’ll be interested to hear more about the role of histone modifications in how learning and memory occurs in the context of social behavior, and in how social behavior can be inherited through multiple generations, as the result of the Bosco lab research funded by this award.

 

Chromosome Tethering in Yeast

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

Chromosopone.0102474_350mes 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.

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”.

Now available: genome stability

genomestablilityProfessor of Biology Jim Haber‘s new book, Genome Stability: DNA Repair and Recombination, five years in the making, has appeared in print this month. The table of contents and a sample chapter can be checked out on the publisher’s website. As always, check Jim’s website (or PubMed) to see new research from the lab. New this month in Nature Structural & Molcular Biology: Dynamics of yeast histone H2A and H2B phosphorylation in response to a double-strand break.

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Eapen wins HHMI International Student Research Fellowship

Vinay Eapen from the Haber Lab in Biology has been awarded an HHMI International Student Research Fellowship. These fellowships, highly sought-after, are among the few available to international students studying at major research universities in the US – there were only 42 recipients nationwide. Eapen is a graduate student entering his fourth year in the Molecular and Cell Biology PhD program at Brandeis, and already has 4 publications from Brandeis to his credit resulting from his studies of the DNA damage checkpoint and autophagy in yeast.

 

Haber 70th Bday Symposium on May 31/Jun 1

Jim Haber as a young professorWe’re holding a 70th Birthday Celebration for Jim Haber on Friday and Saturday this week (May 31 and June 1, 2013). Haber lab members past and present, as well of some of Jim’s colleagues and collaborators, will be giving talks to celebrate the occasion. Come learn about DNA repair and wish Jim a happy birthday! Talks will be held in the Shapiro Campus Auditorium, starting with keynote speaker Fred Alt at 1:15 Friday. The full speaker list is available.

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