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Genome Integrity Discussion Group (1)


for Members

Genome Integrity Discussion Group (1)

Monday, June 19, 2017

The New York Academy of Sciences, 7 World Trade Center, 250 Greenwich St Fl 40, New York, USA

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).


Nonmember Academia, Faculty, etc.
Nonmember Corporate, Other
Nonmember Not for Profit
Nonmember Student, Undergrad, Grad, Fellow
Member Student, Post-Doc, Fellow


Genome Integrity Discussion Group (1)
Scott Keeney, PhD, Memorial Sloan Kettering Cancer Center
Genome Integrity Discussion Group (1)
Susan Smith, PhD, NYU Langone Medical Center
Genome Integrity Discussion Group (1)
Lorraine Symington, PhD, Columbia University Irving Medical Center
Genome Integrity Discussion Group (1)
Sonya Dougal, PhD, The New York Academy of Sciences
Genome Integrity Discussion Group (1)
Caitlin McOmishh, PhD, The New York Academy of Sciences

Keynote Speaker

Genome Integrity Discussion Group (1)
Stephen J. Elledge, Harvard Medical School


June 19, 2017

1:30 PM

Welcome Remarks


Sonya Dougal, PhD
The New York Academy of Sciences
Susan Smith, PhD
NYU Langone Medical Center
1:40 PM

Keynote Address: How Aneuploidy Drives Cancer


Stephen J. Elledge, PhD
Harvard Medical School
2:30 PM

Coffee Break and Poster Set-up


3:00 PM

Nuclear Actin Polymerization Drives DNA Double-Strand Break Clustering for Homology-Dependent Repair


Benjamin Schrank
Columbia University Medical Center (Gautier lab)
3:20 PM

LEM Domain Proteins Control Adaptation by Modulating a Transcription-Dependent Change in Gene Copy Number


Paolo Colombi, PhD
Yale University (King lab)

LEM Domain Proteins Control Adaptation by Modulating a Transcription-Dependent Change in Gene Copy Number

Paolo Colombi, Yale University, Department of Cell Biology

While loss of genome integrity is at the basis of numerous pathologies, including cancer, genome plasticity is necessary to adapt to a changing environment and thus is essential for long-term organismal success. One of the ways in which genomic plasticity manifests is through gene copy number variation (CNV)(Yona, Frumkin, and Pilpel 2015). Historically, the events leading to CNV have been conceptualized through a Darwinian lens as incidental mutations that become fixed in the population because of a fitness advantage. Our work challenges this view; we will present data supporting a targeted mechanism that promotes adaptation to environmental stress by driving site-specific genome instability. We have identified hypervariable protein coding regions in S. cerevisiae by integrating SNP and fragile site distribution across the genome. One such region encodes a cluster of four nearly identical genes (ENA) each coding for a P-type ATPase pump involved in the extrusion of Li+ from the cell; ENA gene expression is induced by growth in high salt concentrations. Interestingly, the load of SNPs near the ENA gene cluster is highly enriched at the 3′ end, which is also an established fragile site; these observations suggest a possible role for ENA gene transcription as a driver of local genome instability. Indeed, a genome stability assay links the fragility of the 3′ end of the ENA gene cluster to both transcription (induced by high salt) and the formation of DNA:RNA hybrids. In chronically high salt conditions, we find that the ENA locus undergoes reproducible gene copy number expansion. Interestingly, we find that the ENA gene cluster is associated with the nuclear periphery in normal growth conditions but moves to the nuclear interior upon exposure of cells to high salt.

To begin to probe if and how CNV of the ENA gene cluster is tied to association with the nuclear periphery, we focused on the LEM domain proteins (Heh1, Heh2); HEH1 and HEH2 genetically interact with genes responsible for transcription-dependent genome instability and Heh1 plays a role in maintaining the stability of the repetitive rDNA (Mekhail et al. 2008). Using an in vitro evolution assay based on prolonged exposure of cells to high concentration of LiCl, we observe that different genotypes (WT, heh1Δ, heh2Δ, heh1Δheh2Δ) adapt at different rates and through distinct pathways, involving CNV and/or point mutations. Taken together, our data suggest the existence of a LEM domain protein-mediated mechanism by which an immediate transcriptional response to a changing environment drives targeted genome instability to promote long-term adaptation through CNV. These results suggest a Lamarckian pathway to promote targeted genome instability in response to a changing environment on which Darwinian selection can act to promote adaptation.

Coauthors: Diane King, Jessica F. Johnston, C. Patrick Lusk, and Megan C. King, Yale University, Department of Cell Biology


Mekhail, Karim, Jan Seebacher, Steven P Gygi, and Danesh Moazed. 2008. "Role for Perinuclear Chromosome Tethering in Maintenance of Genome Stability" 456 (7222). Nature Publishing Group: 667-70. doi:10.1038/nature07460.

Yona, Avihu H, Idan Frumkin, and Yitzhak Pilpel. 2015. "A Relay Race on the Evolutionary Adaptation Spectrum." Cell 163 (3): 549-59. doi:10.1016/j.cell.2015.10.005.

3:40 PM

ALT Phenotypes in ATRX Null Cells Induced by Cohesion Loss and Telomere Damage


Courtney Lovejoy, PhD
The Rockefeller University (de Lange lab)
4:00 PM

Capturing the Onset of Polycomb Domain Formation


Ozgur Oksuz
NYU Langone School of Medicine (Reinberg lab)

Capturing the Onset of Polycomb Domain Formation
Ozgur Oksuz, NYU Langone School of Medicine (Reinberg lab)

The means by which epigenetically inheritable, repressed chromatin domains are established and maintained for appropriate gene expression in mammals remains largely unknown. Polycomb repressive complex 2 (PRC2) maintains transcriptional inactivity by catalyzing tri-methylation of histone H3 at lysine 27 (H3K27me3) within chromatin. Through the design of a system whereby PRC2-mediated repressive domains can be collapsed and then reconstructed in an inducible fashion in vivo, a two-step mechanism of domain formation became evident. First, PRC2 is recruited to a limited number of "nucleation sites" that are enriched for local CpG islands (CGIs), distinguished from other CGIs by the presence of specific motifs. These nucleation sites lie in close spatial proximity, forming polycomb foci within the nucleus. Second, via binding to its catalytic product, PRC2 spreads both locally and distally via long-range contacts to form H3K27me3-chromatin domains. These mechanistic insights into the establishment and maintenance of polycomb-repressive domains across the genome point to the centrality of the 3D chromatin structure.

Coauthors: Varun Narendra1, 2, Chul-Hwan Lee1, 2, Nicolas Descostes1, 2, Gary LeRoy1, 2, Ramya Raviram3, Kelly Karch4, Pedro R. Rocha3, Benjamin A. Garcia4, Jane A. Skok3, and Danny Reinberg1, 2.

1. Howard Hughes Medical Institute, New York University School of Medicine.
2. Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine.
3. Department of Pathology, New York University School of Medicine.
4. Epigenetics Program, Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania.

To whom correspondence should be addressed:

4:20 PM

Closing Remarks


Susan Smith, PhD
NYU Langone Medical Center
4:25 PM

Poster Session and Networking Reception

6:00 PM


To view full attendee list, you must first register for the event, then log in to the Academy website. This list is provided for the personal, noncommercial and informational use only of event attendees, in a manner that is consistent with the New York Academy of Sciences’ mission, goals and activities.
  • ABC Resource

  • Albert Einstein College of Medicine

  • Brooklyn College

  • City College of New York

  • City Univ of New York School of Medicine

  • City University of New York, Brooklyn College

  • Columbia University

  • Columbia University Irving Medical Center

  • Columbia University Medical Center

  • Columbia. University

  • Cornell

  • de Lange Lab

  • Dept of Biochemistry

  • Harvard Medical School

  • Hunter College

  • Hunter College- The City University of New York

  • Icahn School of Medicine at Mount Sinai

  • Institute for Cancer Genetics, Columbia University

  • LPD, Health Marketing

  • Memorial Sloan Kettering

  • Memorial Sloan Kettering Cancer Center

  • Memorial Sloan-Kettering Cancer Center


  • MSKCC, Jasin Lab


  • New York University

  • New York University School of Medicine

  • NYU

  • NYU Biology

  • NYU Langone Medical Center

  • NYU School of Medicine


  • Pfizer, Inc.

  • Princeton University

  • Radiation Oncology

  • Reed College

  • Regeneron

  • Regeneron Pharmaceuticals, Inc

  • Rockfeller University

  • Rutgers University

  • st. johns university

  • Stony Brook University

  • SUNY Downstate Medical Center

  • SUNY Stony Brook

  • The Columbia University School of Medicine

  • The Ohio State University

  • The Rockefeller University

  • The State University of New York

  • Weill Cornell Medical College

  • Weill Cornell Medicine

  • Yale University

  • Yale University School of Medicine