Genome Integrity Discussion Group Meeting (4)

Genome Integrity Discussion Group Meeting

Monday, December 1, 2014

The New York Academy of Sciences

Presented By

Presented by the Genome Integrity Discussion Group at the New York Academy of Sciences.

 

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.

Registration Pricing

Member$0
Member (Student / Postdoc / Resident / Fellow)$0
Nonmember$40
Nonmember (Student / Postdoc / Resident / Fellow)$20


The Genome Integrity Discussion Group is proudly supported by

  • Columbia University CPS
  • Memorial Sloan Kettering Cancer Center
  • NYU Langone Medical Center
  • Rockefeller University


Mission Partner support for the Frontiers of Science program provided by   Pfizer

Agenda

* Presentation titles and times are subject to change.


December 1, 2014

1:30 PM

Welcome and Introductory Remarks
Sonya Dougal, PhD, The New York Academy of Sciences
Susan Smith, PhD, NYU Langone Medical Center

1:40 PM

Recruitment and Spreading of Condensin Complexes in C. Elegans
Sevinc Ercan, PhD, New York University

2:10 PM

Loss of ATRX in ALT Suppresses Resolution of Telomere Cohesion to Control Recombination
Susan Smith, PhD, NYU Langone Medical Center

2:40 PM

Mechanism of DNA Interstrand Crosslink Processing by Repair Nuclease FAN1
Renjing Wang, PhD, Memorial Sloan-Kettering Cancer Center

2:55 PM

Networking Coffee Break

3:25 PM

Visualizing Dynamic Kinetochore Structure Using Super-Resolution Microscopy
David J. Wynne, PhD, The Rockefeller University

3:40 PM

RNA-Programmed Genome Reorganization in the Ciliate Oxytricha
Laura Landweber, PhD, Princeton University

4:10 PM

The Regulation of Genome Replication
Xiaolan Zhao, PhD, Memorial Sloan-Kettering Cancer Center

4:40 PM

Closing Remarks
Susan Smith, PhD, NYU Langone Medical Center

4:45 PM

Networking Reception

5:30 PM

Adjourn

Speakers

Organizers

Scott Keeney, PhD

Memorial Sloan-Kettering Cancer Center

Susan Smith, PhD

NYU Langone Medical Center

Susan Smith, PhD, is Professor in the department of Pathology and the Skirball Institute at the NYU School of Medicine. Her research is focused on human telomeres and the mechanisms that control their function in normal cells, stem cells, and cancer. In particular she is studying shelterin, the six-subunit complex that coats telomere repeats and tankyrase 1, a poly(ADP-ribose) polymerase that associates transiently with telomeres. Areas of research in the lab include: 1) regulation of shelterin and tankyrase 1 stability by post-translational modification, including poly(ADP-ribosyl)ation and ubiquitylation; 2) mechanisms that control establishment of sister telomere cohesion during DNA replication and its resolution in mitosis; 3) the role of defective telomere cohesion in the human stem cell disease dyskeratosis congenita; 4) cell cycle regulation and non-telomeric functions of tankyrase 1 and 5) overlapping and/or distinct roles of tankyrase 2. In addition to being program coordinator in the Skirball Institute, she is director of the NYU genome integrity training program.

Lorraine Symington, PhD

Columbia University Medical Center

Sonya Dougal, PhD

The New York Academy of Sciences

Speakers

Sevinc Ercan, PhD

NYU

Sevinc Ercan is an assistant professor at the Department of Biology and Center for Genomics and Systems Biology, New York University. Sevinc received her BS from Bilkent University in Ankara, Turkey. During her PhD, she worked with Robert Simpson and Jerry Workman on chromatin structure and recombination in yeast. She did her postdoctoral research with Jason Lieb at University of North Carolina, Chapel Hill. There, she found that the condensin-like dosage compensation complex represses transcription by binding to transcriptionally active promoters on the X chromosome in C. elegans. Currently Sevinc studies the molecular mechanisms by which Structural Maintenance of Chromosomes (SMC) protein complexes that include condensin and cohesin regulate chromosome structure and transcription.

Laura Landweber, PhD

Princeton University

Laura Landweber is a Professor of Biology in the Department of Ecology & Evolutionary Biology at Princeton University. Before joining the faculty at Princeton, she was a Junior Fellow of the Harvard Society of Fellows. She has authored over 130 publications in molecular and evolutionary biology and edited 3 books, in areas ranging from genetics and evolution to biological computation. She has served on various panels, working groups, and advisory committees for the NSF, NIH, NHGRI, and NASA and co-chaired the NHGRI Comparative Genome Evolution Working Group from 2003-2007. She is currently Co-Editor-in-Chief of Biology Direct (biology-direct.com), a journal experimenting with open, signed peer review. She is on the editorial board of Genome Biology and Evolution and Eukaryotic Cell and served as Councilor for the Society for Molecular Biology and Evolution from 2007-2009. Recent awards include a Guggenheim fellowship (2012) and a Blavatnik award for young scientists (2008), and she was elected a Fellow of AAAS for probing the diversity of genetic systems in microbial eukaryotes, including scrambled genes, RNA editing, variant genetic codes, and comparative genomics. Her work investigates the origin of novel genetic systems. Recent discoveries include the ability of small and long non-coding RNA molecules to transmit heritable information across generations, bypassing the information encoded in DNA.

Susan Smith, PhD

NYU Langone Medical Center

Susan Smith, PhD, is Professor in the department of Pathology and the Skirball Institute at the NYU School of Medicine. Her research is focused on human telomeres and the mechanisms that control their function in normal cells, stem cells, and cancer. In particular she is studying shelterin, the six-subunit complex that coats telomere repeats and tankyrase 1, a poly(ADP-ribose) polymerase that associates transiently with telomeres. Areas of research in the lab include: 1) regulation of shelterin and tankyrase 1 stability by post-translational modification, including poly(ADP-ribosyl)ation and ubiquitylation; 2) mechanisms that control establishment of sister telomere cohesion during DNA replication and its resolution in mitosis; 3) the role of defective telomere cohesion in the human stem cell disease dyskeratosis congenita; 4) cell cycle regulation and non-telomeric functions of tankyrase 1 and 5) overlapping and/or distinct roles of tankyrase 2. In addition to being program coordinator in the Skirball Institute, she is director of the NYU genome integrity training program.

Renjing Wang, PhD

Structural Biology Program and Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center

Renjing Wang is a postdoctoral fellow supervised by Dr. Nikola P. Pavletich in the Structural Biology Program at Memorial Sloan Kettering Cancer Center. She received her BS and MS in China, and her PhD degree in Biochemistry from the University of Texas Health Science Center at San Antonio. While pursuing her PhD, she focused on the structure and function of the epigenetics gene silencers known as Polycomb Group proteins, and was particularly interested in the assembly and targeting of the Polycomb repression complex 1 related complexes. During her postdoctoral training, she has focused on the structural biology of FAN1 Nuclease and its mechanism of DNA interstrand crosslink processing.

David J. Wynne, PhD

Laboratory of Chromosome and Cell Biology, The Rockefeller University

David Wynne is currently doing postdoctoral work on chromosome segregation in mitosis in Dr. Hiro Funabiki's lab at Rockefeller University. He did his graduate work with Dr. Abby Dernburg at UC Berkeley where he studied chromosome dynamics during meiosis in C. elegans. His interest in molecular biology began as an undergraduate at Amherst College, under the mentorship of Dr. Caroline Goutte. During a short break from lab research, David taught science in New York as a teacher at Saint Ann's School in Brooklyn. He hails from the great state of New Jersey.

Xiaolan Zhao, PhD

Memorial Sloan-Kettering Cancer Center

Xiaolan Zhao conducted her graduate research with Rodney Rothstein at Columbia University, and postdoc research with Gunter Blobel at Rockefeller University. Her graduate work identified a novel protein inhibitor of dNTP synthesis and revealed how checkpoint-mediated regulation of dNTP levels impacts growth. Her postdoc work identified the conserved Smc5/6 complex and its SUMO ligase function in yeast, and elucidated how nuclear pores regulate sumoylation. Her lab currently studies various regulatory mechanisms that enable faithful genome duplication and repair. The lab uses a versatile combination of molecular, genetic, biochemical, cell biological, and genomic/proteomic approaches. Discovery highlights include the elucidation of Smc5/6 biochemical properties and its master roles in recombination intermediate metabolism, as well as how SUMO directs the DNA stress response and dynamically regulates DNA repair, telomere length and repetitive DNA stability. Future work will both deepen the understanding of these processes and explore new regulatory mechanisms in replication and repair.

Sponsors

For sponsorship opportunities please contact Perri Wisotsky at pwisotsky@nyas.org or 212.298.8642.

Academy Friend

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The Genome Integrity Discussion Group is proudly supported by

  • Columbia University CPS
  • Memorial Sloan Kettering Cancer Center
  • NYU Langone Medical Center
  • Rockefeller University

Abstracts

Recruitment and Spreading of Condensin Complexes in C. Elegans
Sevinc Ercan, PhD, Department of Biology, New York University

Condensins are multi-subunit protein complexes that are essential for chromosome condensation during mitosis and meiosis, and play key roles in transcription regulation during interphase. Metazoans contain two condensins (I and II), which perform different functions and localize to different chromosomal regions. C. elegans contains a third condensin (DC) that is targeted to and represses transcription of the X chromosome for dosage compensation. Our analyses of condensin I, II, and DC binding in C. elegans show that condensins bind to a subset of active promoters, tRNA genes and putative enhancers, as well as unannotated intergenic sites. The mechanisms by which condensins are targeted to their genomic binding sites remain unclear. Our work indicates that condensin binding is established in two-steps: recruitment and spreading. Recruitment is DNA sequence specific and determined in part by sequence motifs that may be bound by recruiter proteins. Spreading is not sequence specific and occurs onto a subset of active promoters and other intergenic sites. Here, we will present the results form our ectopic recruitment studies using condensin DC, to understand the factors involved in X–specific recruitment. We will also briefly discuss condensin DC spreading, which increases the level of H4K20me1, a mitosis associated histone modification, and this results in transcription repression.
 

Loss of ATRX in ALT suppresses resolution of telomere cohesion to control recombination
Susan Smith, The Skirball Institute, New York University School of Medicine, New York, NY

The chromatin-remodeling factor ATRX is the protein most frequently lost in tumors that use the recombination based, alternative lengthening of telomeres (ALT) mechanism for telomere maintenance, but its role in telomere recombination is not known. We found that loss of ATRX suppresses resolution of sister telomere cohesion at mitosis. In the absence of ATRX, the histone variant macroH2A1.1 binds to the PARP tankyrase 1, preventing it from localizing to telomeres and from resolving cohesion. Restoration of sister telomere resolution by overexpression of tankyrase 1 (or the macroH2A1.1-binding domain of ATRX) results in rampant recombination between non-sister telomeres, genomic instability, and impaired cell growth, indicating that keeping sister telomeres in close proximity into mitosis is essential for the ALT cell state. The newly identified ATRX-macroH2A1.1-tankyrase axis may provide a novel therapeutic target in ALT tumors.
 
Coauthor: Mahesh Ramamoorthy, The Skirball Institute, New York University School of Medicine, New York, NY
 

Mechanism of DNA Interstrand Crosslink Processing by Repair Nuclease FAN1
Renjing Wang1

DNA interstrand crosslinks (ICLs) are highly toxic lesions associated with cancer and degenerative diseases. ICLs can be repaired by the Fanconi Anemia (FA) pathway and through FA-independent processes involving the FAN1 nuclease. Here, FAN1-DNA crystal structures and biochemical data reveal that human FAN1 cleaves DNA successively at every third nucleotide. In vitro, this exonuclease mechanism allows FAN1 to excise an ICL from one strand through flanking incisions. DNA access requires a 5’-terminal phosphate anchor at a nick or 1-2 nucleotide flap, and is augmented by a 3’ flap, suggesting FAN1 action is coupled to DNA synthesis or recombination. FAN1’s mechanism of ICL excision is well suited for processing other localized DNA adducts as well.
 
Coauthors: Nicole S. Persky1, Barney Yoo2, Ouathek Ouerfelli2, Agata Smogorzewska3, Stephen J. Elledge4,5, Nikola P. Pavletich1
 
1. Structural Biology Program and Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
2. Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
3. Laboratory of Genome Maintenance, The Rockefeller University, New York, NY 10065, USA
4. Department of Genetics and Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA
5. Division of Genetics, Brigham and Women’s Hospital, Boston, MA 02115, USA

 

Visualizing Dynamic Kinetochore Structure Using Super-Resolution Microscopy
David J. Wynne, Laboratory of Chromosome and Cell Biology, The Rockefeller University, New York, NY 10065, USA

During chromosome segregation, the function of kinetochores changes from interacting with the lateral surfaces of microtubules and activating the spindle assembly checkpoint (SAC) to capturing microtubule ends and silencing the SAC. The molecular mechanism that couples this functional change to microtubule attachment status remains unclear. Although the molecular identity of kinetochore components has now been well established, we have just begun to understand the assembly process and spatial arrangement of this dynamic machine.  Applying 3-D super-resolution imaging to Xenopus egg extracts, we reveal that the kinetochore is spatially and functionally segmented into a stable core module supporting end-on attachment and an expandable module responsible for lateral attachment and SAC signaling. Unexpectedly, the inner kinetochore component CENP-C is an integral component of the expandable module, whose assembly also depends on outer kinetochore proteins (Bub1, BubR1) and multiple protein kinases (Aurora B, Haspin, Plx1, Mps1) and is suppressed by protein phosphatase 1.  We propose that the expandable module consists of a phosphorylation-dependent copolymer that spatially segregates kinetochore functions to help couple end-on attachment and SAC silencing.
 
Coauthor: Hironori Funabiki, Laboratory of Chromosome and Cell Biology, The Rockefeller University, New York, NY 10065, USA
 

RNA-programmed genome reorganization in the ciliate Oxytricha
Laura Landweber, Princeton University, Princeton NJ

The ciliate Oxytricha possesses a dynamic pair of genomes, and massive DNA rearrangements produce a highly fragmented but functional somatic genome from a complex germline genome. This process eliminates nearly all noncoding DNA, including transposons, and rearranges over 225,000 short DNA segments to produce tiny gene-sized "nanochromosomes." In the precursor germline genome, the shattered segments of different genes often interweave with each other, frequently overlap and sometimes combinatorially assemble (Chen et al. 2014 Cell 158:1187). The whole process produces a mature, somatic genome of over 16,000 nanochromosomes (Swart et al., 2013 PLoS Biology 11: e1001473).  Noncoding RNAs regulate the entire process of genome rearrangement. Maternally-inherited, long, non-coding (lnc) RNAs provide three layers of continuity across generations, including serving as templates for both genome remodeling and RNA-guided DNA repair (Nowacki et al., 2008 Nature 451:153) while also regulating gene dosage and chromosome copy number (Nowacki et al., 2010 PNAS 107:22140). This illustrates the ability of lncRNAs to transmit heritable changes to the next generation. Furthermore, 27nt piRNAs provide the critical information to mark and protect the retained DNA segments of the genome (Fang et al., 2012 Cell 151:1243). Together, Oxytricha's elaborate epigenome, assembled through complex interacting networks of both long and small non-coding RNAs, encapsulates an RNA-driven world packaged in a modern cell. The mechanism for all of these dynamic actions bypasses the traditional modern pathway of inheritance via DNA, hinting at the power of RNA molecules to sculpt genomic information.
 

The regulation of genome replication
Lisa Hang, Wei Tan, Xiaolan Zhao, Department of Molecular Biology, Memorial Sloan Kettering Cancer Center, New York, USA

DNA replication is a highly regulated process that is essential for preserving the integrity of the genome. To cope with endogenous and exogenous sources of replication stress, a network of regulatory factors is evolved to facilitate synthesis over damaged or blocked template DNA.  Some are DNA metabolism enzymes that physically remove lesions or blocks from templates. Others are protein modification enzymes that can change the properties of many proteins at once to elicit changes in favor of replication. A third group is scaffolds that can establish specific molecular associations with enzymes or other factors that are required for overcoming replication obstacles. How each of these factors functions during replication and how they coordinate are important questions to understand in order to decipher the sophisticated and multi-facets replication regulation. We will present some current findings from our lab using the budding yeast as a model system to address these questions.
 

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