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Genome Integrity Discussion Group June 2012


for Members

Genome Integrity Discussion Group June 2012

Monday, June 4, 2012

The New York Academy of Sciences

Presented By


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 John Petrini (Memorial Sloan Kettering Cancer Center), and Rodney Rothstein and Lorraine Symington (Columbia University). This meeting will include a scientific symposium from 2:00 to 5:00 PM, followed by a networking reception from 5:00 to 7:00 PM.

Call for Student Presentation Abstracts: Deadline May 25th
Four students and/or postdocs will be selected from abstracts submitted throughout the year for short talks. Submitters of the remaining abstracts are invited to present posters. Abstracts should be in CSHL format with file name: and submitted via email to Dr. John Petrini at by Friday, May 25th.

Registration Pricing

Student / Postdoc / Fellow Member$0
Student / Postdoc / Fellow Nonmember$15


* Presentation times are subject to change.

Monday June 4, 2012

2:00 PM

John Petrini, PhD, Memorial Sloan-Kettering Cancer Center

2:10 PM

Keynote address: Live Imaging of Chromatin Mobility During DNA Repair
Susan M. Gasser, PhD, Friedrich Miescher Institute for Biomedical Research, Switzerland

3:00 PM

Coffee break and poster set-up

3:40 PM

Role of the RNaseH2 Complex and the Srs2 Helicase in Maintaining Genome Stability
Catherine Potenski, PhD, (Klein lab, New York University School of Medicine)

4:00 PM

Mre11-dependent DNA Damage Response in Oncogene Induced Breast Tumorigenesis
Gaorav Gupta, MD, PhD (Petrini lab, Memorial Sloan-Kettering Cancer Center)

4:20 PM

Single-Molecule Studies of Non-Homologous End Joining: Formation and Dynamics of Synaptic Complexes
Dylan A. Reid, MS (Rothenberg lab, New York University School of Medicine)

4:40 PM

Dual Functions of RecO in the Single-Strand Annealing and Homologous Recombination Pathways of Mycobacteria
Richa Gupta, PhD (Glickman and Shuman labs, Memorial Sloan-Kettering Cancer Center)

5:00 PM

Poster Session and Networking Reception

7:00 PM




John Petrini, PhD

Memorial Sloan-Kettering Cancer Center

Rodney Rothstein, PhD

Columbia University Medical Center

Lorraine Symington, PhD

Columbia University Medical Center

Keynote Speaker

Susan M. Gasser, PhD

Friedrich Miescher Institute for Biomedical Research, Switzerland

Prof. Susan M. Gasser is the director of the Friedrich Miescher Institute for Biomedical Research, a position she assumed in 2004. In addition, Susan Gasser was appointed to a professorship at the University of Basel. Her research activities are pursued at the Friedrich Miescher Institute.

Before joining the Friedrich Miescher Institute for Biomedical Research, Susan Gasser was a Professor of Molecular Biology at the University of Geneva. For the preceding 15 years she had led a research group at the Swiss Institute for Experimental Cancer Research.

Susan Gasser's research interests focus on how nuclear organization impinges on mechanisms of repair and replication fork stability and on epigenetic inheritance of cell fate decisions. Her laboratory combines genome-wide mapping, synthetic lethal screens, quantitative live fluorescence imaging, biochemical reconstitution and standard yeast molecular genetics to address these questions at the molecular and cellular levels. In questions of stem cell determination and epigenetic inheritance, the Gasser group works with C. elegans, to study the effects of nuclear organization on gene expression during well-characterized cell differentiation events. She has authored more than 250 primary articles and reviews over the last 30 years. She has received a number of awards for her work, including election to the Académie de France, the Swiss Medical Academy and Academia Europaea. She received the FEBS | EMBO Women in Science Award 2012, the Inserm International Prize in 2011, and both the Otto Naegeli Award and the Gregor Mendel Medal in 2006.

Susan M. Gasser studied at the University of Chicago (B.A. Honors in Biophysics) and at the University of Basel (PhD in Biochemistry). She did her postdoctoral studies with U.K. Laemmli at the University of Geneva.

Susan serves on numerous review boards and advisory councils throughout Switzerland and Europe including the European Union FP7 Health Sciences Advisory Board, the Nestle Nutrition Council and from 2001 -2004, as chairman of the EMBO Council.


Gaorav Gupta

Petrini lab, Memorial Sloan-Kettering Cancer Center

Richa Gupta

Glickman and Shuman labs, Memorial Sloan-Kettering Cancer Center

Catherine Potenski

Klein lab, New York University School of Medicine

Dylan A. Reid

Rothenberg lab, New York University School of Medicine


Academy Friend


Live Imaging of Chromatin Mobility during DNA Repair
Susan M. Gasser, PhD, Friedrich Meischer Institute for Biomedical Research, Basel, Switzerland

The nucleus is highly organized and several specialized subcompartments have been described in the context of transcription. For example, in budding yeast, nuclear pores are highly conductive to transcription, whereas other regions of the nuclear periphery facilitate gene repression. How chromatin moves to these subnuclear regions remains unclear. Using quantitative fluorescence microscopy in live budding yeast, we addressed the mechanistic requirements for chromatin movement. We found that chromatin movement can occur independently of transcription elongation and instead seems to be driven by chromatin remodeling. Indeed, targeting subunits of the ATP-dependent chromatin remodeling complex INO80 to chromatin increases the volume that a tagged locus can explore. This effect was entirely dependent on the ATPase activity of the complex. Furthermore, we found that increased chromatin movement increases the rates of homologous recombination between distant sequences. To examine further the dynamics of DNA damage, we scored the mobility of a site-specific double-strand break both by LacI-GFP tracking and by following the focus formed by the binding of Rad52-YFP. The locus clearly moves faster and is less constrained than the same undamaged locus, exploring nearly half of the nuclear volume within minutes. The increase in chromatin mobility is lesion-specific since Rad52-YFP foci induced by a single site-specific protein-DNA adduct remain constrained. We show that the increase in movement requires the INO80 subunit Arp8, the homologous recombination proteins Rad51 and Rad54, and the DNA damage response mediators Mec1 and rad9. Consistent with a role for chromatin movement in the homology search step of homologous recombination, we find that appearance of recombination intermediates between a double-strand break and an ectopic template is delayed in rad9 mutant cells. Taken together, our data suggest that chromatin movement promotes the critical step of homology search during homologous recombination, is driven by chromatin remodeling, and is regulated by the DNA damage response perhaps to avoid gratuitous recombination with ectopic sequences, which can generate deleterious translocations and cancer.

Mre11-dependent DNA Damage Response in Oncogene Induced Breast Tumorigenesis
Gaorav Gupta, MD, PhD, Petrini lab, Memorial Sloan-Kettering Cancer Center

Oncogene expression has been associated with activation of a DNA damage response (DDR) in multiple cellular systems. However, the molecular pathways that mediate DDR activation, as well as the functional significance of this pathway in tumor suppression remain poorly characterized. We utilized the MMTV-TVA/RCAS model of Neu/Her2-inducible breast cancer to demonstrate that oncogene expression in adult mammary epithelial cells results in activation of a DDR in vivo. To determine the functional significance of the DDR in constraining breast tumorigenesis, we interbred the MMTV-TVA strain with multiple DDR mouse mutants that have previously been characterized to have deficiencies in DDR-induced checkpoint activation and/or apoptosis. These mutants included Chk2-/-, Nbs1ΔC/ΔCChk2-/-, p53515C/515C, and Mre11ATLD/ATLD. Whereas disruption of apoptosis to varying degrees has no impact on tumorigenesis, the Mre11ATLD/ATLD hypomorphic allele is associated with significantly more frequent and accelerated onset of mammary tumors. Furthermore, the tumors that emerge in the Mre11ATLD/ATLD mutant mice exhibit high-grade histological features, and give rise to disseminated lung metastases. By examining the early stages of oncogene-induced hyperplasia, we observe that the DDR is no longer activated in Mre11ATLD/ATLD animals. Additionally, whereas oncogene expression activates a G2/M checkpoint and induces expression of senescence-associated heterochromatin in the WT background, both of these tumor suppressive activities are significantly impaired in the Mre11ATLD/ATLD mutant. In summary, we demonstrate that in vivo expression of a relevant oncogene in mammary epithelium results in Mre11-dependent activation of a DDR, and suggest that the G2/M checkpoint is more important than apoptosis in oncogene-dependent mammary tumor suppression, via activation of a senescence-like program.

Dual Functions of RecO in the Single-Strand Annealing and Homologous Recombination Pathways of Mycobacteria
Richa Gupta, PhD, Glickman and Shuman labs, Memorial Sloan-Kettering Cancer Center

Lesions in DNA such as double-strand breaks (DSBs) are lethal to all life forms and diverse mechanisms of repair exist in different organisms to ensure genome integrity. In the model bacterium, Escherichia coli, DSB repair is achieved by homologous recombination (HR) wherein the resection nuclease RecBCD first acts on the DSB ends to produce long single-stranded 3’ tails on to which it then recruits the strand-exchange protein RecA. We recently showed that mycobacteria, that include the human pathogen M. tuberculosis, rely on two more options to reseal DSBs, namely, non-homologous end joining (NHEJ) and single-strand annealing (SSA). The DNA-end binding protein Ku and ligase D constitute the primary components of the NHEJ machinery, and SSA requires RecBCD, which surprisingly has no role in mycobacterial HR. In lieu, a heterodimeric nuclease, AdnAB, participates in HR, but even in the absence of both AdnAB and RecBCD, substantial cellular HR (50%) is still maintained. This guided us to investigate the RecA-loading machinery active in the cell that facilitates HR. We specifically examined the role of RecO in mycobacterial DSB repair. Our data show that RecO functions as a mediator in RecA dependent HR in a pathway parallel to the AdnAB pathway. In addition, we find that RecO plays a critical role in the RecA independent SSA pathway. Consistent with the in vivo findings, the mycobacterial RecO protein displays a strong zinc dependent DNA binding activity and accelerates the annealing of SSB coated single stranded DNA. However, in contrast to E. coli RecO, mycobacterial RecO catalyzes SSA without interacting with the SSB C-terminal tail. These findings establish a novel role for RecO in two pathways of mycobacterial DSB repair and provide an in vivo function for the DNA annealing activity of bacterial RecO proteins, thereby strongly extending the functional orthology between RecO and yeast Rad52.

Role of the RNaseH2 Complex and the Srs2 Helicase in Maintaining Genome Stability
Catherine Potenski, PhD, Klein lab, New York University School of Medicine

Srs2 protein has both DNA helicase and Rad51 nucleofilament activities in vitro. Most of the in vivo phenotypes of srs2Δ mutants are associated with failure to remove Rad51 nucleofilament (Rad51 strippase) and prevent toxic recombination events. Here we show an in vivo role for the DNA helicase activity of Srs2 in mutation avoidance and genome integrity, in the context of rNMP misincorporation into DNA. The presence of RNA in the genome, via misincorporation of ribonucleotides or the failure to remove lagging strand-associated RNA primers, can lead to genetic instability. RNaseH2 activity, or the targeted digestion of DNA:RNA hybrids, is important for the clearance of potentially mutagenic RNA residues from the genome. Here we examine the phenotypes of RNaseH2 mutants with various mutants of the SRS2 helicase. Our results suggest that Srs2 helicase acts on rNMP substrates that are not removed by RNaseH2, in a Top1-dependent reaction, to prevent mutation. rnh202Δ srs2Δ double mutants are slow growing, hyper-recombinogenic and enriched in doublet cells, indicative of partial G2 checkpoint arrest. They are synergistically sensitive to hydroxyurea (HU) and have increased Rad52 foci, markers of double-stranded breaks. Additionally, the mutation rates of rnh202Δ srs2Δ double mutants are increased above the levels of the single mutants alone. These phenotypes are rescued by a truncation mutant of SRS2 bearing the helicase domain (srs2-860), while an ATPase-dead mutant of SRS2 that encodes a non-functioning helicase phenocopies the null mutation (srs2-KA-860). This suggests an in vivo role for Srs2 as a helicase, independent from both the Rad51-strippase activity of Srs2 and its interaction with SUMOylated PCNA. The mutations generated in rnh202Δ srs2Δ double mutants are mostly slippage events in 1-5bp short repeat sequences, which are signature mutations of transcription-mediated Top1-dependent events. We find that top1Δ mutants suppress rnh202Δ srs2Δ mutant phenotypes, including HU sensitivity, high recombination levels and the increased mutation rates. To help determine the contribution of the Srs2 helicase specifically to dinucleotide slippage mutations, we examined reporter assays containing dinucleotide repeats. We observed significant increases in mutation rates in the rnh202Δ srs2Δ and rnh202Δ srs2-KA-860 double mutant cells in comparison to rnh202Δ alone or rnh202Δ srs2-860 cells. This leads us to the model whereby the helicase activity of Srs2 mitigates Top1-dependent damage that is generated when RNaseH2 fails to remove RNA residues from DNA.

Single-Molecule Studies of Non-Homologous End Joining: Formation and Dynamics of Synaptic Complexes
Dylan A. Reid, MS, Rothenberg lab, New York University School of Medicine

Non-Homologus End Joining (NHEJ) is one of the two conserved pathways employed to repair double stranded DNA breaks in all domains of life. Central to this pathway in H. sapiens, is the protein hetrodimer Ku 70/86. Ku recognizes free DNA ends and recruits numerous other proteins to facilitate repair of the break. Current models for NHEJ require a minimum of DNA Ligase IV and XRCC4 (LX), as well as DNA dependent Protein Kinase catalytic subunit (DNA-PKcs). Recent studies showed that the protein XLF/Cernunnos can mediate NHEJ, substituting DNA-PKcs. Here we use single-molecule Fluorescence Energy Transfer (smFRET) to probe the dynamics of synaptic complex assembly on free DNA ends. We initially establish that Ku 70/86, LX, and XLF give rise to highly stable end-to-end joining, even on substrates that are incapable of ligation. On substrates capable of undergoing ligation, we notice that complex formation is vastly improved over the substrates lacking 5' phosphates. Our method provides a novel and direct measure of how well components of NHEJ bring together free DNA ends. It also provides us with the ability to monitor the rearrangements of the complex in real time, enabling to resolve the fine details of NHEJ, that are otherwise masked in ensemble methods.

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