Genome Integrity Discussion Group

Genome Integrity Discussion Group

Monday, October 3, 2016

The New York Academy of Sciences

The connection between cancer and genome integrity is widely appreciated. Importantly, the greater New York Metropolitan area is unparalleled in the concentration of world leading research on chromosome biology and function, as well as for research at the interface between chromosome integrity and the dynamics of malignancy. The Genome Integrity Discussion Group capitalize on this concentration of excellence, providing a forum for interaction between basic- and clinically-oriented research groups working in these fields. These meetings not only facilitate synergy between labs, but also provide a context in which previously unappreciated complementarities can 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. At each of the meetings, two early career scientists (students or postdocs) are selected to present data.

Genome Integrity Discussion Group meetings are organized under the leadership of Susan Smith (NYU Langone Medical Center), Lorraine Symington (Columbia University Medical Center), and Scott Keeney (Memorial Sloan Kettering Cancer Center).

Call for Student/Postdoc Presentation Abstracts: Deadline September 9, 2016

Two abstracts will be selected for short talks by students/postdocs. Please submit in CSHL format with file name NYAS.name.doc via email to Prof Smith at Susan.Smith@med.nyu.edu by September 9th, 2016.

Registration Pricing

Member$0
Member (Student / Postdoc / Resident / Fellow)$0
Nonmember (Academia)$65
Nonmember (Corporate)$75
Nonmember (Non-profit)$65
Nonmember (Student / Postdoc / Resident / Fellow)$30

Agenda

* Presentation times are subject to change.


Monday, October 3, 2015

1:30 PM

Welcome and Introductory Remarks
Caitlin McOmish, PhD, The New York Academy of Sciences
Susan Smith, PhD, NYU School of Medicine

1:40 PM

Reconstructing Shattered Cancer Genomes
Marcin Imielinski, MD, PhD, Weill Cornell Medicine

2:10 PM

Ubiquitin-like E3 Ligase Activities in Replication / Repair
Christopher Lima, PhD, Memorial Sloan Kettering Cancer Center

2:40 PM

Cooperation Between a Hierarchical Set of Recruitment Sites Specifically Targets the C. elegans Dosage Compensation Complex to the X Chromosomes
Sarah Albritton, New York University

2:55 PM

Coffee Break

3:25 PM

Single-Molecule Analysis of mtDNA Replication Uncovers the Basis of the Common Deletion
Aaron Fraser Phillips, NYU School of Medicine, Sackler Institute

3:40 PM

At the Intersection of DNA Damage and Immune Responses
Barry Sleckman, MD, PhD, Weill Cornell Medicine

4:10 PM

Effect of DNA Damage on Chromatin Positional Dynamics
Alexandra Zidovska, PhD, New York University

4:40 PM

Networking Reception

5:30 PM

Adjourn

Organizers

Scott Keeney, PhD

Memorial Sloan Kettering Cancer Center

Susan Smith, PhD

NYU Langone Medical Center

Lorraine Symington, PhD

Columbia University Irving Medical Center

Sonya Dougal, PhD

The New York Academy of Sciences

Caitlin McOmish, PhD

The New York Academy fo Sciences

Speakers

Sarah Albritton

Sarah Albritton is a PhD candidate in the laboratory of Dr. Sevinc Ercan at New York University. Her work focuses on elucidating the mechanism of condensin recruitment in the context of the C. elegans dosage compensation complex.

Marcin Imielinski, MD, PhD

Weill Cornell Medicine

Marcin Imielinski, MD, PhD, is an Assistant Professor of Computational Genomics and Assistant Professor of Pathology and Laboratory Medicine at Weill Cornell Medicine. He holds a joint appointment as a Core Member and Assistant Investigator at the New York Genome Center. Dr. Imielinski's research interests are in applying high-throughput sequencing and computation to study patterns of somatic genomic variation in cancer. He is specifically interested in probing long-range cancer genome structure through the use of cutting-edge sequencing protocols and the development of novel machine learning and data visualization approaches.

Dr. Imielinski received a BS in Computer Science from Rutgers College in 2000. He obtained a PhD in genomics and computational biology and his MD from the University of Pennsylvania School of Medicine in 2008. He completed his residency in pathology at the Massachusetts General Hospital in 2011, and a fellowship in molecular genetic pathology at Harvard Medical School in 2012. Prior to joining Weill Cornell and NYGC, he was a postdoctoral fellow in computational cancer genomics at the Broad Institute of Harvard and MIT, under the mentorship of Drs. Matthew Meyerson and Gad Getz.

Christopher Lima, PhD

Memorial Sloan Kettering Cancer Center

Christopher D. Lima is a Professor and Member of the Structural Biology Program at Sloan Kettering Institute in New York City and an Investigator of the Howard Hughes Medical Institute. He is also a Professor of Biochemistry and Structural Biology at the Weill Cornell Graduate School of Medical Sciences. He received his PhD in 1994 from Northwestern University and completed his postdoctoral studies in 1998 as a Helen Hay Whitney Fellow at Columbia University. His research focuses on essential eukaryotic processes ranging from 5' and 3' RNA processing to post-translational modification and signaling by ubiquitin-like proteins.

Aaron Phillips

Sfeir Lab, Sackler Institute at NYU Langone Medical Center

Aaron Phillips obtained a BS in Chemistry from Union College in 2006 and a MS in Chemistry from Tufts University in 2012. That same year, Aaron started his PhD at the Sackler Institute at NYU Langone Medical Center, where he joined the laboratory of Dr. Agnel Sfeir to investigate mitochondrial DNA replication and its impairment leading to mtDNA aberrancies.

Barry Sleckman, MD, PhD

Weill Cornell Medicine

Dr. Barry Sleckman completed his MD and PhD (Immunology) at Harvard Medical School in 1990 followed by an internship and residency in Medicine and a fellowship in Infectious Diseases at the Brigham and Women's Hospital in Boston. In 1998, after completing a post-doctoral fellowship in Molecular Immunology in the laboratory of Dr. Frederick Alt at Harvard Medical School, Dr. Sleckman started as an Assistant Professor in the Department of Pathology and Immunology at the Washington University School of Medicine (WUSM) in St. Louis. His laboratory focuses on elucidating pathways required for immune system development and on understanding DNA damage responses, especially as they apply to cancer and the development of novel cancer therapeutics. In 2015 he moved his laboratory to Weill Cornell Medical College where he is the Vice Chairman of the Department of Pathology and Laboratory Medicine.

Alexandra Zidovska, PhD

New York University

Alexandra Zidovska

Prof. Zidovska is an experimental physicist studying physical phenomena in biological systems and materials. She received her Diploma in Physics (M.Sc.) in 2003 from Technical University Munich in Germany, where she studied under supervision of Prof. Erich Sackmann.  She used reflection interference contrast microscopy (RICM) and magnetic tweezers to study micromechanical properties of filopodia and cell membrane of macrophages. She received her PhD in 2008 from University of California, Santa Barbara, where she worked in the lab of Prof. Cyrus Safinya in the Materials Department. Her doctoral work focused on the studies of the structure-function relationship of lipid-DNA self-assemblies used for gene delivery. She investigated liquid crystalline structures of lipid-DNA self-assemblies and phase behavior of exotic highly charged dendrimer lipids using small angle X-ray scattering (SAXS), confocal microscopy and cryogenic transmission electron microscopy (cryoTEM). She then conducted her post-doctoral research at Harvard University, where she worked jointly in the lab of Prof. Timothy Mitchison at Harvard Medical School and Prof. David Weitz in Physics Department at Harvard University. In her postdoctoral research she developed a method Displacement Correlation Spectroscopy (DCS), which allows for the first time to map and quantify chromatin positional dynamics in interphase (time between two cell divisions) simultaneously across an entire nucleus. DCS employs high-resolution spinning disc confocal microscopy and measures chromatin displacements by image-correlation over the entire nucleus, and the entire temporal spectrum of the experiment, which probes chromatin dynamics at different time- and length-scales. Previously, only movement of single genes or foci had been tracked. DCS revealed collective chromatin dynamics across the entire nucleus, which paints a new physical picture of chromatin organization, and opens new avenues in chromatin research. Prof. Zidovska held prestigious Damon Runyon Cancer Research Fellowship 10'-12' and is a recipient of the National Institutes of Health Pathway to Independence Award.

Abstracts

Single-Molecule Analysis of mtDNA Replication Uncovers the Basis of the Common Deletion
Aaron F. Phillips, Skirball Institute of Biomolecular Medicine, Department of Cell Biology, NYU School of Medicine
 
Mutations in mitochondrial DNA (mtDNA) lead to mitochondrial dysfunction, a chief cause of muscular and neurological diseases and a major contributor to human aging. The most frequent mitochondrial aberrancy is a 4977 base-pair deletion — known as the common deletion — that cripples oxidative phosphorylation. Key to the genesis of this deletion are two flanking repeats that can promote replication slippage or aberrant double-strand break (DSB) repair. To interrogate how this toxic lesion forms, we developed a novel single-molecule DNA combing method to examine mtDNA replication at high resolution. The analysis of replicating mtDNA molecules provided in vivo evidence in support of the asymmetric mode of replication. Notably, we observed frequent fork stalling in the vicinity of the common deletion in cells expressing disease-associated mutations in the mitochondrial helicase, Twinkle. In parallel experiments, we induced breaks in distinct loci of the mitochondrial genome using mito-TALENs and found that breaks adjacent to the 5′ flanking repeat result in the common deletion. Interestingly, this process was mediated by the mitochondrial replisome and independent of canonical DSB repair proteins. Based on our data, we propose a model whereby a unique replication-dependent repair pathway operates in the mitochondria to induce the common deletion. Understanding the basis of this widespread aberrancy is an essential first step to prevent its accumulation in mitochondrial diseases.
 
Coauthors: Armêl Millet2, Marco Tigano1, Sonia M. Dubois2, Hannah Crimmins1, Loelia Babin2, Marine Charpentier2, Marion Piganeau2, Erika Brunet2, and Agnel Sfeir1.
 
1. Skirball Institute of Biomolecular Medicine, Department of Cell Biology, NYU School of Medicine.
2. Structure et Instabilité des Génomes, Muséum National d'Histoire Naturelle, Inserm Paris.

At the intersection of DNA Damage and Immune Responses
Barry P. Sleckman, Weill Cornell Medical College

DNA double strand breaks (DSBs) are dangerous lesions that can lead to cellular transformation if resolved aberrantly as chromosomal translocations or deletions. DSBs are generated by genotoxic agents and as intermediates during important physiologic processes such as antigen receptor gene assembly in developing lymphocytes and the modification of antigen receptor genes in mature B lymphocytes. We have shown previously that through the activation of DNA damage responses (DDR), these DSBs can regulate cellular activities that are important for normal lymphocyte development and for the function of mature lymphocytes. We have also shown that DSBs generated by genotoxic agents produced by innate immune cells also activate a DDR that regulates important innate immune responses. Recent developments in these areas will be discussed.
 
Coauthor: Abigail Morales, Weill Cornell Medical College

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