Genome Integrity Discussion Group October 2015
Monday, October 5, 2015
The New York Academy of Sciences
Presented by the Genome Integrity Discussion Group
The greater New York Metropolitan area has become a leading center for research on chromosome biology and function, as well as for research at the interface between chromosome integrity and onset and progression of malignancy. The connection between cancer and genome integrity is widely appreciated, and the concentration of excellence in this field is unparalleled anywhere in the world. The Genome Integrity meetings are designed to provide a forum for interactions between the many basic science and clinically-oriented research groups working on these issues. We feel that these interactions will not only facilitate synergy between labs, but also provide a context in which previously unappreciated complementarities will be revealed.
In that spirit, the talks will cover a broad range of areas, including, but not limited to the DNA damage response and cancer predisposition, DNA replication, transcription, chromatin modification, recombination, cell cycle control, telomeres, chromosome segregation, epigenetic states, as well as the emergence of new technologies relevant to research in genome integrity. Although a primary focus is upon basic mechanisms and processes, these areas are pertinent to cancer and myriad human disease states, and it is expected that this will be reflected in the substance of our discussions.
Genome Integrity Discussion Group meetings are organized under the leadership of Scott Keeney (Memorial Sloan Kettering Cancer Center), Susan Smith (NYU Langone Medical Center) and Lorraine Symington (Columbia University). This meeting will include a scientific symposium from 1:30 to 4:30 PM, followed by a networking reception from 4:30 to 5:30 PM.
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* Presentation titles and times are subject to change.
October 5, 2015
Welcome and Introductory Remarks
Mechanisms of ALT Telomere Recombination
Building the Meiotic Chromosome Axis
Genome-Wide Analysis of DNA End Resection During Yeast Meiosis
A Damage Independent Role for 53BP1 that Impacts Chromatin Organization of Igh and Retrotransposons
Revealing the Impact of the Nuclear Environment on DSB Resection Using a Live Cell Assay
RAD51, the DNA Damage Checkpoint and Increased Chromosome Mobility in Diploid Saccharomyces Cerevisiae
Susan Smith, PhD
NYU Langone Medical Center
Scott Keeney, PhD
Memorial Sloan-Kettering Cancer Center
Lorraine Symington, PhD
Columbia University Medical Center
Eleni Mimitou, PhD
Memorial Sloan Kettering Cancer Center
Eleni Mimitou is a postdoctoral fellow in the laboratory of Dr. Scott Keeney at Memorial Sloan Kettering Cancer Center, where she studies repair of programmed DNA double strand breaks using yeast as a model system. She earned her undergraduate degree in Pharmaceutical Sciences at the Aristotle University of Thessaloniki before pursuing her Ph.D. at Columbia University, where she carried out her thesis work under the supervision of Dr. Lorraine Symington. Eleni was a Helen Hay Whitney Foundation Postdoctoral Fellow from 2012-2015.
Pedro Rocha, PhD
NYU Langone Medical Center
I have received a strong undergraduate education in both microbiology and genetics. During my PhD, mouse genetics and development were the main of focus of my studies. My PhD was part of an EU research training network named “Systems Biology of Nuclear Receptors”. This strongly influenced my PhD project and stirred it into the fields of gene regulation, which has always been a great interest of mine. During my PhD I became fascinated with cell biology, mainly with studies concerning nuclear organization and how DNA localization and accessibility is controlled. In line with this interest of mine is the research pursued in the Skok lab. Research in the Skok lab adds to a growing body of evidence that long-range interactions play a dynamic role in regulating gene expression, but this clearly remains an underexplored area of epigenetic regulation. My post-doctoral training here has provided me with the tools necessary to understand the influence of nuclear organization in gene regulation and introduce me to the fascinating fields of immunology and genomic stability. Using these tools I have already been able to show how the nuclear architecture of B cells influences the generation of chromosomal translocations that can act as driver mutations in lymphoma. I am now involved in deciphering the precise molecular and epigenetic mechanisms that B cells use to ensure that during Class Switch Recombination (CSR) DNA double strand breaks (DSBs) are correctly introduced and repaired.
Rodney Rothstein, PhD
The Rothstein lab primarily focuses on the biological responses to DNA damage. Using budding yeast as a model system, we are particularly interested in the genes and pathways involved in DNA double-strand break (DSB) and crosslink repair. We pioneered the use of recombination to alter genomes and our work on plasmid-chromosome recombination led us and our collaborators to formulate the DSB repair model for genetic recombination. We developed “one-step” gene disruption technology in yeast, the foundation for “knock-out” technology in many organisms. We discovered conserved genes affecting the control of genome stability including Top3, a novel eukaryotic type I topoisomerase and Sgs1, a DNA helicase, whose human homologues (Blm, Wrn and Rts) cause cancer predisposition and/or premature aging. By combining genetics and cell biology to study the choreography of the DNA damage response, we detailed precise cellular responses to both spontaneous and induced DNA damage in living cells. Using fluorescently tagged proteins, we developed yeast strains to follow events from the initiation of the damage event through its repair. We demonstrated that recombination foci assemble at chromosome breaks and act as repair centers capable of repairing more than one DSB. We are currently studying chromosome movement during this process.
Roger Greenberg, MD, PhD
University of Pennsylvania
Roger Greenberg, MD, PhD is an Associate Professor in the Department of Cancer Biology at the Perelman School of Medicine at the University of Pennsylvania. He also serves as Director of Basic Science at the Basser Research Center for BRCA at the University of Pennsylvania. Dr. Greenberg’s research is focused on homology directed DNA repair and its relationship to cancer etiology and response to therapy. His laboratory has made important contributions to these areas by defining ubiquitin dependent recognition of DNA double-strand breaks, communication between DNA damage responses and transcription, mechanisms of alternative telomere length maintenance, and BRCA1 dependent DNA repair processes that contribute to the suppression of hereditary breast and ovarian cancer. This body of work has led to the identification of three cancer cancer susceptibility genes and the designation of biallelic mutation to the BRCA1 gene as a cause of a new Fanconi Anemia Subtype.
Megan King, PhD
Megan C. King is an Associate Professor of Cell Biology at the Yale School of Medicine. Her research focuses on LINC complexes - macromolecular complexes that span the nuclear envelope to physically couple the nucleus and the cytoskeleton. These molecular bridges allow the cytoskeleton to regulate nuclear position within the cell. In addition, they provide a mechanism for signals to be mechanically transduced between the cytoplasm and nucleus. Her research includes investigating how the association of DNA double strand breaks with the nuclear periphery (and in particular the LINC complex) impacts genome integrity. Her group also investigates the role that the nucleus plays in tissue level mechanics, particularly focusing on the skin, and has developed live-cell and force spectroscopy assays to define the mechanical behaviour of nuclei. She is the recipient of the NIH New Innovator Award and was named a Searle Scholar in 2011.
Andreas Hochwagen, PhD
New York University
Dr. Hochwagen received his M.S. in Chemistry from the University of Vienna, Austria, and his Ph.D. in Cell Biology from the Massachusetts Institute of Technology where he investigated the checkpoint mechanisms of meiotic recombination in the budding yeast, Saccharomyces cerevisiae. He continued this work as an independent research fellow at the Whitehead Institute in Cambridge, MA, where he also developed novel experimental approaches to monitor meiotic chromosome structure and chromosome breakage. Dr. Hochwagen joined the Department of Biology at New York University in 2011 as an Assistant Professor. His research currently focuses on understanding the structure and dynamics of meiotic chromosomes as well as probing the internal architecture of repetitive DNA arrays.
Genome-wide analysis of DNA end resection during yeast meiosis
Eleni Mimitou*, Shintaro Yamada and Scott Keeney
Howard Hughes Medical Institute, Molecular Biology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA
*Helen Hay Whitney Foundation Fellow
In most sexually reproducing organisms, homologous recombination initiated by double-strand breaks (DSBs) lies at the heart of meiosis by promoting proper segregation of homologous chromosomes. During recombination, the 5’-terminal strands of each DSB are processed (end-resected) to reveal the ssDNA necessary to then identify a homologous repair template. DSBs are introduced by the transesterase Spo11 in dispersed regions along the chromosomes (concentrated in so-called hotspots). Spo11 forms a covalent complex with DSB ends as part of the cleavage reaction, and is then endonucleolytically released as the initial step of end resection. DNA removed by DSB processing is reconstituted by DNA synthesis, which copies genetic information from the intact homologous template. The coordinated degradation and re-synthesis of DNA dictate homology usage and determine repair product configuration and, although they reside in the heart of the recombination pathway, they are not well understood. For that reason we sought to develop a novel assay that would allow us to study DNA end resection genome-wide at high spatial resolution during yeast meiotic recombination. The assay relies on the fact that removal of the ssDNA tails of resected DSBs marks the position where resection stopped. Molecular features of resection are revealed by sequencing of these ssDNA-to-dsDNA junctions and comparison to high-resolution DSB maps made by sequencing of short DNA oligonucleotides covalently bound to Spo11. Bioinformatic analysis of the sequencing results and construction of individual and genome-wide resection maps is exposing interesting, unforeseen features of this fundamental and highly conserved process. Our analysis extends to hypo- and hyper-resection mutants in our attempt to obtain mechanistic insights. Mathematical modeling of a simple two-step resection process as described from genetic studies is not enough to predict the patterns we derive from our maps. Based on our results we propose that end-resection is heavily context dependent and chromosomal features such as chromatin structure may shape the resection landscape.
A Damage Independent Role for 53BP1 that Impacts Chromatin Organization of Igh and
Pedro Rocha, Ramya Raviram, Yi Fu, JungHyun Kim, Arafat Aljoufi, Emily Swanzey, Vincent Luo, Alessandra Pasquarella, Alessia Balestrini, John Petrini, Gunnar Schotta and Jane Skok.
When programmed DNA breaks generated during B cell development are not properly repaired, chromosomal translocations can occur that might lead to activation of oncogenes, malignant transformation, and ultimately lymphomas. I will show how lymphocytes use epigenetic mechanisms to prepare for the introduction of these breaks to ensure successful recombination and avoid genomic instability. I will also demonstrate how these same mechanisms minimize the mutagenic potential of transposons, which are another source of genomic instability for B lymphocytes and other cell types.
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