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Genome Integrity Discussion Group April 2016

Genome Integrity Discussion Group April 2016

Monday, April 4, 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 Lorraine Symington (Columbia University Medical Center), Scott Keeney (Memorial Sloan Kettering Cancer Center), and Susan Smith (NYU Langone Medical Center).

Registration Pricing

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


* Presentation times are subject to change.

Monday, April 4, 2016

1:30 PM

Welcome and Introductory Remarks
Caitlin McOmish, PhD, The New York Academy of Sciences
Lorraine Symington, PhD, Columbia University Medical Center

1:40 PM

PHF11 Promotes EXO1-dependent DSB Resection and ATR Signaling
Titia deLange, PhD, The Rockefeller University

2:10 PM

Inner Workings of the UvrA•UvrB DNA Damage Sensor
David Jeruzalmi, PhD, The City College of New York – CUNY

2:40 PM

A Diffusion Concentration Gradient Model for Replication Origin Firing in Fission Yeast
Atanas Kaykov, PhD, The Rockefeller University (Nurse Lab)

2:55 PM

Coffee Break

3:25 PM

Fan1 Deficiency Results in DNA Interstrand Crosslink Repair Defects, Enhanced Tissue Karyomegaly, and Organ Dysfunction
Supawat Thongthip, The Rockefeller University (Smogorzewska Lab)

3:40 PM

DNA Condensation by MukB and Topoisomerase IV
Ken Marians, PhD, Memorial Sloan Kettering Cancer Center

4:10 PM

Specific and Redundant Roles for Pif1 Helicases in the Maintenance of Genome Integrity
Duncan Smith, PhD, New York University

4:40 PM

Closing Remarks
Lorraine Symington, PhD, Columbia University Medical Center

4:45 PM


5:30 PM



Scott Keeney, PhD

Memorial Sloan Kettering Cancer Center

Susan Smith, PhD

NYU Langone Medical Center

Lorraine Symington, PhD

Columbia University Medical Center

Sonya Dougal, PhD

The New York Academy of Sciences

Caitlin McOmish

The New York Academy of Sciences


Titia deLange, PhD

The Rockefeller University

Dr. Titia de Lange—Leon Hess Professor, Director of the Anderson Center for Cancer Research, and head of the laboratory for Cell Biology and Genetics at the Rockefeller University—studies telomeres, the protective elements at the ends of chromosomes. Dr. de Lange's group was instrumental in the discovery and analysis of shelterin, the protein complex that binds to telomeres and prevents DNA damage signaling and inappropriate DNA damage repair at chromosome ends. Dr. de Lange is the recipient of the 2014 Gairdner International Award, the 2013 Breakthrough Prize in Life Sciences, and the 2012 Dr. H.P. Heineken Prize for Biochemistry and Biophysics. She is a member of the Royal Dutch Academy of Sciences, the European Molecular Biology Organization, the American Academy of Arts and Sciences, and is a foreign associate of the National Academy of Sciences and a member of the National Academy of Science Institute of Medicine.

David Jeruzalmi, PhD

The City College of New York – CUNY

The Jeruzalmi group is broadly interested in the molecular mechanisms that underlie the faithful transmission of genetic information. We are currently focused on two areas, the machinery associated with DNA replication initiation and 2) nucleotide excision repair. A large body of work has described the associated complexes and details of how they operate. And yet, something as fundamental as a three-dimensional image of the active entity in various stages of operation remains elusive. The goal of research in my laboratory is to provide a structural view of these "machines" and, by concomitant application of biochemical approaches, to provide a fundamental understanding of the underlying mechanisms. We are working with eukaryotic and bacterial entities, with the idea that parallel analysis will enable extraction of fundamental principles. Control of DNA replication initiation and genome integrity are central to cell growth and are frequently damaged in cancer. Understanding the structures of the associated protein complexes will spur development of new therapeutics.

Atanas Kaykov, PhD

The Rockefeller University (Nurse Lab)

Ken Marians, PhD

Memorial Sloan Kettering Cancer Center

Kenneth J. Marians, PhD, is a New York City native, born in Brooklyn. He attended the Polytechnic Institute of Brooklyn as an undergraduate majoring in Chemistry and received a BS degree (Magna cum Laude) in 1972. He was a graduate student with Ray Wu at Cornell University, receiving his PhD in Biochemistry in 1976 for studies on the structure of the lac operator and the development of various molecular cloning techniques such as using oligonucleotides as linkers. As a postdoctoral fellow with Jerard Hurwitz at the Albert Einstein College of Medicine he established the role of the topoisomerase DNA gyrase in the replicative life cycle of bacteriophage фX174. He started his independent research career in 1978 as an Assistant Professor at Albert Einstein in the Department of Developmental Biology and Cancer and was promoted to Associate Professor in 1983.

In 1984 he moved to the Molecular Biology Program of the Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, where he was promoted to Member in 1988. He has been Chairman of the Molecular Biology Program since 1991 and was the founding (and current) Dean of the Louis V. Gerstner, Jr. Graduate School of Biomedical Sciences. His early research centered on how the activities of the replisome were governed by interactions between the various component proteins and the roles of the type I and type II topoisomerases in DNA replication.

Recent studies have focused on the role of topoisomerase IV in chromosome segregation and DNA packaging and condensation. He was one of the founders of the field of replication restart, proposing in 1991 that the replication protein, PriA, was required to restart replication forks that had stalled because of collisions with endogenous template damage. Subsequently he defined the biochemical pathways of origin-independent, DNA structure-specific replication restart, and discovered the ability of the replisome to skip over lesions in the leading-strand template, a reaction that indicated that the replisome was inherently DNA damage tolerent.

Duncan Smith, PhD

New York University

Duncan Smith has been an Assistant Professor of Biology at New York University since 2013. Prior to joining NYU, he obtained a BA from Cambridge University (2004) and a PhD from the Rockefeller University (2009) where he worked on substrate specificity in pre-mRNA splicing under the supervision of Magda Konarska. From 2009–2013 he was a postdoctoral fellow with Iestyn Whitehouse at Memorial Sloan-Kettering, where he developed genomic methods to analyze Okazaki fragment properties and distributions. Awards include a Damon Runyon postdoctoral fellowship (2010), the March of Dimes Basil O'Connor Starter Scholar award (2015), and the Searle Scholars Program (2015).

Supawat Thongthip

The Rockefeller University (Smogorzewska Lab)

Supawat Thongthip is a graduate fellow in the laboratory of Dr. Agata Smogorzewska at the Rockefeller University, where he studies the mechanism of DNA interstrand crosslink repair and the in vivo consequences of deficiency in the repair process. Before joining Agata's lab, Supawat earned his undergraduate degree in Molecular and Cellular Biochemistry from the University of Oxford, where he carried out his Master's thesis work in the lab of Prof. Kim Nasmyth.


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Columbia University

Memorial Sloan Kettering Cancer Center

NYU Langone Medical Center

Rockefeller University


Inner Workings of the UvrA•UvrB DNA Damage Sensor
David Jeruzalmi, PhD, The City College of New York

Efficient elimination of DNA lesions by the nucleotide excision repair (NER) pathway is critical for all organisms. In bacteria, the NER pathway is implemented by the successive action of three proteins, UvrA, UvrB and UvrC via a series of large and dynamic multi-protein complexes. A large number of studies have defined three major stages associated with the early steps of the NER pathway. In stage 1, a large (300–400 kDa) complex of the UvrA and UvrB proteins (AB) scans the genome to identify lesion-containing DNA. This process requires rapid binding and release of DNA; moreover, damage must be specifically recognized, and distinguished from native DNA, despite the fact that the relevant lesions induce widely different DNA structures. Once lesion-containing DNA has been located, it is stably bound by a dimeric form of UvrA within the AB complex (Stage 2). A major reorganization then occurs in which UvrA is lost from the ensemble, and concomitantly, UvrB becomes localized at the site of damage (Stage 3). Following these early stages, additional events lead to excision of the damage on one strand, and repair of the resulting single-stranded gap.
We have determined several structures of UvrA and the UvrA•UvrB complex. These structures provoke a critical re-examination of the mechanism of the early stages of bacterial NER, and suggest a revised reaction with several unanticipated features.

A Diffusion Concentration Gradient Model for Replication Origin Firing in Fission Yeast
Atanas Kaykov, The Rockefeller University

We developed a new DNA combing method that allows the investigation of replicating single DNA molecules up to the size of full-length fission yeast chromosomes. Improving the scale of observation by more than one order of magnitude has allowed us to show that the majority of origins fire stochastically forming clusters of closely spaced origins. However, replication origins across the fission yeast genome fire with varying efficiency: some origins are very efficient (fire every other cell cycle) while others are very inefficient (fire every 10–20 cell cycles). We asked if the spatial positioning of replication origins within the nucleus might influence their firing efficiencies.
We built a coarse-grained polymer model for fission yeast chromosomes which integrates empirical measurements for: chromosome flexibility, chromosome contact of unlinked loci captured by proximity-ligation techniques (Hi-C), the constrained position of centromeres and mating type locus at the Spindle Pole Body (SPB, centrosome equivalent structure in fungi) and of telomeres at nuclear periphery. The model predicts spatial segregation between efficient and inefficient origins, because efficient origins are located close to the nuclear center while inefficient origins are enriched in the nuclear periphery. This organization is dependent upon histone 3 lysine 9 methylation (H3K9me) since in clr4Δ (histone 3 Lysine 9 methyl transferase) cells the model predicts reciprocal shift in the localization of early and late origins (model integrates Hi-C data established for clr4Δ cells). We tested this prediction of our model by analyzing origin firing efficiencies in clr4Δ cells and showed that origin efficiencies are globally reprogrammed in clr4Δ cells. Specifically, efficient origins became inefficient and some inefficient origins became more efficient. Moreover, our model predicts a correlation between efficiency of origin usage and distance from the SPB. Therefore, we propose a model for stochastic origin firing in which limiting origin activation factors are switched on in the vicinity of SPB and then diffuse throughout the nucleus activating origins of replication.
Coauthors: Justin O'Sullivan2 and Paul Nurse1,3.
1. Yeast Genetics and Cell Biology, The Rockefeller University.
2. Liggins Institute, University of Auckland.
3. Cell Cycle Laboratory, The Francis Crick Institute, London.

Fan1 Deficiency Results in DNA Interstrand Crosslink Repair Defects, Enhanced Tissue Karyomegaly, and Organ Dysfunction
Supawat Thongthip, The Rockefeller University

Deficiency of FANCD2/FANCI-associated nuclease 1 (FAN1) in humans leads to karyomegalic interstitial nephritis (KIN), a rare hereditary kidney disease, characterized by chronic renal fibrosis, tubular degeneration and characteristic polyploid nuclei in multiple tissues. The mechanism of how FAN1 protects cells is largely unknown but is thought to involve FAN1's function in DNA interstrand crosslink (ICL) repair. Here, we describe a Fan1 deficient mouse and show that FAN1 is required for cellular and organismal resistance to ICLs. We show that the UBZ domain of FAN1, which is needed for interaction with FANCD2, is not required for the initial rapid recruitment of FAN1 to ICL or for its role in DNA ICL resistance. Epistasis analyses reveal that FAN1 has crosslink-repair activities that are independent of the Fanconi anemia proteins and that this activity is redundant with the 5′–3′ exonuclease, SNM1A. Karyomegaly becomes prominent in kidneys and livers of Fan1 deficient mice with age and mice develop liver dysfunction. Treatment of Fan1 deficient mice with ICL-inducing agents results in pronounced thymic and bone marrow hypocellularity and disappearance of c-kit+ cells. Our results provide insight into the mechanism of FAN1 in ICL repair and demonstrate that the Fan1 mouse model effectively recapitulates the pathological features of human FAN1 deficiency.
Coauthors: Marina Bellani2, Siobhan Gregg1, Sunandini Sridhar1, Brooke Conti1, Yanglu Chen1, Michael Seidman2, and Agata Smogorzewska1.
1. Laboratory of Genome Maintenance, The Rockefeller University.
2. Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health.

Specific and Redundant Roles for Pif1 Helicases in the Maintenance of Genome Integrity
Duncan Smith, PhD, New York University

Pif1 helicases are a conserved family present in both prokaryotes and eukaryotes. While most eukaryotes encode just one, Saccharomyces cerevisiae encodes two distinct Pif1-family helicases—Pif1 and Rrm3—which have been reported to play distinct roles in numerous nuclear processes. We describe the systematic characterization of the roles of Pif1 helicases in replisome progression and lagging-strand synthesis in S. cerevisiae.
We demonstrate a redundant role for Pif1 and Rrm3 in stimulating strand-displacement by DNA polymerase δ during lagging-strand synthesis. Further, we show that Rrm3 and to a lesser extent Pif1, facilitate replisome progression past tRNA genes, which in the absence of both helicases become point replication terminators. Although progress past tRNA genes is impeded in the context of both co-oriented and head-on collisions between replication and tRNA transcription, head-on collisions lead to greater replisome stalling: consistent with this observation, we find that tRNA genes in S. cerevisiae are preferentially oriented to minimize head-on replication-transcription conflicts. In contrast to previous reports, we observe no impact of RNA polymerase II-transcribed genes or G-quadruplexes on replisome mobility in pif1 and/or rrm3 mutants.

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