Genome Integrity Discussion Group April 2014

Speakers

Organizers

John Petrini, PhD

Memorial Sloan-Kettering Cancer Center

Susan Smith, PhD

NYU Langone Medical Center

Susan Smith, PhD, is a Professor in the Skirball Institute and Department of Pathology in the NYU School of Medicine. Prior to joining NYU in 1999 as an Assistant Professor, Dr. Smith trained as a postdoctoral fellow with Dr. Titia de Lange and Dr. Gunter Blobel at The Rockefeller University. She earned her PhD from Stony Brook University working with Dr. Bruce Stillman at Cold Spring Harbor Laboratory. Dr. Smith’s current research focuses on: regulation of telomere protein stability and function by post-translational modifications including poly(ADP-ribosyl)ation and ubiquitylation; mechanisms controlling establishment and resolution of sister chromatid cohesion at telomeres; impact of defective telomere cohesion in the human stem cell disease dyskeratosis congenita; and cell cycle regulation and non-telomeric functions of the PARP tankyrase 1, including its role at spindle poles and centrosomes. The long-term goal of her research is to understand the mechanisms that ensure genome integrity and cell survival. In addition to serving on the Skirball internal advisory committee, she is the Graduate Advisor for the Molecular Oncology and Tumor Immunology Graduate program at NYU and she served as a regular member of the NIH Molecular Genetics B Study Section.

Lorraine Symington, PhD

Columbia University Medical Center

DNA repair mechanisms are essential for the maintenance of genome integrity and defects in these processes are associated with cancer predisposition in humans. Research in the Symington laboratory is focused on three critical aspects of homology-directed double-strand break (DSB) repair: mechanism and regulation of DNA end processing; mechanisms of break-induced replication (BIR); and identification of nucleases involved in maturation of homologous recombination intermediates.  The Symington laboratory has made important contributions to understanding how the ends of double-strand breaks are processed to generate 3’ single-stranded tails and the interplay between non-homologous end joining and the initiation of DNA end resection. These studies paved the way for research in vertebrate systems showing the mechanism of end resection is highly conserved. Their BIR studies were the first to demonstrate Rad51 dependence, that the initial strand invasion intermediate is unstable and for a conservative mode of DNA synthesis during BIR.  They also identified Mus81-Mms4 as the main nuclease responsible for mitotic crossovers in yeast and proposed a novel role for the Rad1-Rad10 (XPF-ERCC1 in human) nuclease in cleaving recombination intermediates between ectopic sequences resulting in formation of a single Holliday junction intermediate.

Speakers

Leemor Joshua-Tor, PhD

Cold Spring Harbor Laboratory

Leemor Joshua-Tor, Ph.D. is a Howard Hughes Medical Institute Investigator and Professor at Cold Spring Harbor Laboratory. She uses a combination of biochemistry, molecular biology and biophysics to uncover how cells work at a molecular level. One way she does this is using a method called x-ray crystallography to deduce the structures of proteins, DNA and RNA molecules and determine how they interact, which leads to a better understanding of how these components work to control important cellular events. She is perhaps best known for her groundbreaking work revealing the inner workings of the gene-silencing mechanisms of RNA interference (RNAi), a process that regulates many important cellular processes and is emerging as a powerful took in biotechnology and medicine. She is also known for her studies on the molecular motors that are essential for DNA replication.

Dr. Joshua-Tor was born in Israel and received a B.Sc. in chemistry from Tel-Aviv University and a Ph.D. in chemistry from the Weizmann Institute of Science in Rehovot. She was awarded the presitgious Jane Coffin Childs postdoctoral fellowship for her continued training at the California Institute of Technology prior to joining the CSHL faculty. At CSHL, she was the Director of the Undergraduate Summer Research Program and then the Dean of the Watson School of Biological Sciences, CSHL’s graduate school. She is widely recognized as one of the top scientists in her area, and has been recognized by several awards, including the Dorothy Crowfoot Hodgkin Award from the Protein Society and the Beckman Young Investigator Award. She was recently elected as a Fellow of the American Association for the Advancement of Science. In addition to her research activities, Dr. Joshua-Tor serves on the editorial boards of several international scientific journals and on several advisory committees at the National Institutes of Health.

John Pascal, PhD

Thomas Jefferson University

John M. Pascal, Ph.D., is an Associate Professor of Biochemistry and Molecular Biology and a member of the Kimmel Cancer Center at Thomas Jefferson University, Philadelphia, USA.  He studied the structural biology of DNA replication and repair as a postdoctoral fellow at Harvard Medical School, and earned his Ph.D. at the University of Texas, Austin.  His research currently focuses on proteins involved in maintaining genome stability.

Orlando Scharer, PhD

Stony Brook University

Orlando D. Schärer grew up in Zürich, Switzerland, where he received his MSc in Chemistry from the ETH Zürich. He obtained a PhD in chemistry with Gregory Verdine at Harvard University and conducted postdoctoral studies with Roland Kanaar and Jan Hoeijmakers at Erasmus University in Rotterdam in the Netherlands. He started his independent research group at the University of Zürich, Switzerland, before moving to Stony Brook University, NY in 2005, where he is currently professor of pharmacological sciences and chemistry. His research combines organic chemistry, biochemistry and cell biology to study mechanism of mammalian DNA repair pathways and the relationships of these pathways to genetic disorders, carcinogenesis and antitumor therapy.

Shan Zha, MD, PhD

Columbia University

The Zha lab is interested in the molecular mechanism of DNA double stand break repair and its implications in the development of normal lymphocytes and lymphoid malignancies. The goal of the lab is to use the knowledge in DNA repair understand the etiology of primary immunodeficiency and oncogenic translocations and ultimately facilitate better diagnosis and treatment for leukemia and lymphomas. Normal lymphocyte utilizes programmed DNA breaks as obligated intermediates during the assembly and subsequent modifications of the antigen receptor gene product. While these recombination events are critical for the diversity, specificity and longevity of the adaptive immune responses, mistakes during this process drive oncogenic translocations characteristic for human lymphoid malignancies. While these programmed breaks are initiated by lymphocyte specific genes, the DNA repair and completion of these recombination events rely on ubiquitously expressed DNA damage responsive genes and the non-homologous end-joining pathways. Dr. Zha finished her post-doctoral training in the laboratory of Dr. Frederic Alt and established her own group in Columbia University in 2010. In the past ten years, Dr. Zha and her lab have used mouse genetic approach to understand the role of DNA repair gene deficiencies in primary immunodeficiency and lymphomas. In this process, they have generated mouse models carrying disease causing mutations in DNA damage response genes (e.g. ATM, H2AX) and in members of the non-homologous end-joining pathway (e.g. XLF, DNA-PKcs). Using these tools, they identified extensive crosstalk and redundancies in DNA repair pathways. A subset of the animal models developed spontaneous lymphomas sharing molecular features with human lymphoid malignances.  The Zha lab has characterized the translocation patterns and mechanism and identified novel tumor suppressor genes for acute lymphoblastic leukemias.