Roger A. Greenberg, MD, PhD

faculty photo
Associate Professor of Cancer Biology
Department: Cancer Biology
Graduate Group Affiliations

Contact information
Department of Cancer Biology
Abramson Family Cancer Research Institute
The Perelman School of Medicine at the University of Pennsylvania
421 Curie Boulevard
513 BRB II/III
Philadelphia, PA 19104-6160
Office: 215-746-2738
Fax: 215-573-2486
Lab: 215-746-7799
Education:
BA (Chemistry)
Haverford College, 1991.
Ph.D. (Microbiology and Immunology)
Albert Einstein College of Medicine, 2000.
M.D.
Albert Einstein College of Medicine, 2000.
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Description of Research Expertise

Research Interests
This laboratory is devoted to understanding how basic mechanisms of DNA repair impact cancer etiology and response to targeted therapies. As a focal point to interrogate these interrelationships, we are devoted to the elucidation of BRCA1- and BRCA2- dependent homologous recombination DNA repair mechanisms and their roles in breast and ovarian cancer susceptibility. We have more recently developed an additional focus on cancer associated telomere length maintenance mechanisms that rely on a specialized form of homologous recombination. We utilize a myriad of approaches to investigate these areas, which include biochemistry, structural biology, cell biology, and genetically engineered mouse models.

Key words: BRCA1, BRCA2, ATM, Ubiquitin, DNA repair, Homologous Recombination, Telomeres, Chromatin, Epigenetics, Breast Cancer, Ovarian Cancer.

Description of Research

Germline mutations to the Breast Cancer 1 (BRCA1) or Breast Cancer 2 (BRCA2) genes are the major cause of hereditary breast and ovarian cancer susceptibility. Clinical BRCA1 and BRCA2 mutations render cells deficient in DNA damage checkpoint signaling and error-free mechanisms of DNA repair known as homologous recombination, implicating these activities in tumor suppression.

The BRCA proteins interact with numerous other DNA repair factors in several distinct protein complexes to execute homologous recombination and checkpoint functions. Our work has revealed a partial molecular understanding for how BRCA1 recognizes DNA damage and competes with opposing DNA repair proteins to control genome integrity. We have demonstrated that an interaction between the BRCA1 BRCT domain and the RAP80 ubiquitin binding protein targets BRCA1 to K63-linked ubiquitin structures present at DNA damage sites. The RAP80 ubiquitin interaction motifs (UIMs) provide an ubiquitin recognition element to target the BRCA1 E3 ligase and a K63-ubiquitin specific deubiquitinating enzyme BRCC36 to DNA double strand breaks. Each of these activities is required for appropriate DNA damage checkpoint and repair responses (Sobhian et al. Science 2007; Shao et al. Genes&Dev 2009; Shao et al. PNAS 2009;Tang et al. Nat Struct & Mol Biol 2013). Cancer causing BRCA1 BRCT mutants fail to interact with RAP80 and consequently demonstrate inefficient recruitment to DNA damage sites. Moreover, in collaboration with Dr. Robert Winqvist (University of Oulu, Finland), we have identified germline mutations in RAP80 and Abraxas as a cause of familial breast cancer (Nikkila et al. Oncogene 2009; Solyom et al Sci Transl Med 2012). Thus, a series of ordered events involving ubiquitin recognition, breakdown and synthesis are required for BRCA1-dependent DNA damage responses and tumor suppression.

A second area of interest in the laboratory is the complex relationship between chromatin structure and DNA repair. We have developed several novel systems to investigate interrelationships between chromatin structure and DNA double strand break (DSB) repair (Shanbhag et al. Cell 2010; Cho et al. Cell 2014). This was instrumental to our finding that DSBs induce an ATM kinase dependent transcriptional silencing that spans multiple kilobases of chromatin in cis to the site of DNA damage. This process may have significance towards understanding how the DNA damage response impacts the genesis of chromosome translocations, meiotic sex chromosome inactivation, and viral latency. We have also gained an understanding of how chromatin environment affects DNA repair mechanism choice (i.e. whether a break is repaired by homologous recombination or nonhomologous end-joining). These studies have implicated combinatorial histone modifications in mediating competition between BRCA1 and 53BP1, thus impacting cellular responses to DNA damage inducing targeted therapies such as PARP inhibitors (Tang et al. Nat Struct Mol Biol 2013). More recently, we have discovered a novel form of homology directed repair that is responsible for alternative telomere length maintenance mechanisms in approximately 15% of human cancers (Cho et al. Cell 2014). We will continue to use these systems to investigate how chromatin structure impacts DNA repair mechanism and contributes to genome integrity, cancer etiology and response to therapy.


Rotation Projects
Rotation projects are open to students in each of the areas the lab focuses on. Please see Roger Greenberg to discuss potential rotation projects.


Lab personnel:
Nam Woo Cho - Graduate Student
Robert Dilley - Graduate Student
Qinqin Jiang - Graduate Student
Mischa Li - Graduate Student
Vibhor Gupta - Postdoctoral Researcher
Shane Harding - Postdoctoral Researcher
Lei Tian - Postdoctoral Researcher
Gang Yuan – Postdoctoral Researcher
Junmin Wu - Research Specialist, Lab Manager
Harrison Winters - Research Specialist
Jonathan Boiarsky – Undergraduate Student
Indu Subbaraj – Undergraduate Student

Administrative Coordinator:
Laura Murillo
215-573-0908
murillo@exchange.upenn.edu

Selected Publications

Cho NW, Dilley RL, Lampson MA, Greenberg RA: Interchromosomal Homology Searches Drive Directional ALT Telomere Movement and Synapsis. Cell 159(1): 108-21, September 2014.

Sawyer SL, Tian L, Kahkonen M, Schwartzentruber J, Kircher M, Majewski J, Dyment DA, Innes AM, Boycott KM, Moreau LA, Moilanen JS, Greenberg RA: Biallelic Mutations in BRCA1 Cause a New Fanconi Anemia Subtype. Cancer Discovery December 2014.

Tang J, Cho NW, Cui G, Manion EM, Shanbhag NM, Botuyan MV, Mer G, Greenberg RA: Acetylation limits 53BP1 association with damaged chromatin to promote homologous recombination. Nat Struct Mol Biol 20(3): 317-25, March 2013 Notes: Highlighted in Nature Reviews Mol Cell Biol 2013: Du Toit A. DNA damage: Limiting 53BP1.

Zheng H#, Gupta V#, Patterson-Fortin J#, Bhattacharya S#, Katlinski K, Wu J, Varghese B, Carbone CJ, Aressy B, Fuchs SY*, Greenberg RA*.: A BRISC-SHMT Complex Deubiquitinates IFNAR1 and Regulates Interferon Responses. Cell Reports [Epub ahead of print], 2013 Notes: # co-first author * co-corresponding author.

Domchek SM*, Tang J, Jill Stopfer, Lilli DR, Tischkowitz M, Foulkes WD, Monteiro ANA, Messick TE, Powers J, Yonker A, Couch FJ, Goldgar D, Nathanson KL, Greenberg RA*: Biallelic deleterious BRCA1 mutations in a woman with early-onset ovarian cancer. Cancer Discovery 3(4): 399-405, April 2013 Notes: *co-corresponding authors. Highlighted in Cancer Discovery 2013: D’Andrea AD. BRCA1: A Missing Link in the Fanconi/BRCA Pathway.

Greenberg RA: BRCA1, everything but the RING? Science 334(6055): 459-60, 2012

Solyom S, Aressy B, Pylkäs K, Patterson-Fortin J, Hartikainen JM, Kallioniemi A, Kauppila S, Nikkilä J, Kosma VM, Mannermaa A, Greenberg RA*, Winqvist R*: Recurrent breast cancer predisposition-associated Abraxas mutation disrupts nuclear localization and DNA damage response functions of BRCA1. Science Trans Med 4(122): 122ra-23, 2012 Notes: *Denotes co-corresponding authorship.

Li ML and Greenberg RA: Links between genome integrity and BRCA1 tumor suppression. Trends in Biochem Sci 37(10): 418-24, 2012.

Shanbhag NM, Rafalska-Metcalf IU, Balane-Bolivar C, Janicki SM, and Greenberg RA: ATM dependent chromatin changes silence transcription in cis to DNA Double Strand Breaks. Cell 141: 970-81, June 2010 Notes: Comment in: ATM Creates a veil of transcriptional silence. Cell. 2010 Jun 11;141(6):924-6.

Shao G, Patterson-Fortin J, Messick TE, Feng D, Shanbhag N, Wang Y, Greenberg RA: MERIT40 controls BRCA1-Rap80 complex integrity and recruitment to DNA double-strand breaks. Genes & Development 23(6): 740-54, 2009 Notes: Comment in: Higher-order BRCA1 complexity Nature Reviews Molecular Cell Biology 10, 301-301 (May 2009); and in Cancer Biol Ther. 2009 Apr;8(7):571-2. Penn researchers identify new protein important in breast cancer gene's role in DNA repair.

Shao G, Lilli DR, Patterson-Fortin J, Coleman KA, Morrissey DE, Greenberg RA: The Rap80-BRCC36 de-ubiquitinating enzyme complex antagonizes RNF8-Ubc13-dependent ubiquitination events at DNA double strand breaks. Proceedings of the National Academy of Sciences USA 106(9): 3166-71, 2009.

Schaetzlein S, Kodandaramireddy NR, Ju Z, Lechel A, Stepczynska A, Lilli DR, Clark AB, Rudolph C, Kuhnel F, Wei K, Schlegelberger B, Schirmacher P, Kunkel TA, Greenberg RA, Edelmann W, Rudolph KL: Exonuclease-1 deletion impairs DNA damage signaling and prolongs lifespan of telomere-dysfunctional mice. Cell 130(5): 863-77, 2007.

Sobhian B, Shao G, Lilli DR, Culhane AC, Moreau LA, Xia B, Livingston DM*, Greenberg RA*: RAP80 targets BRCA1 to specific ubiquitin structures at DNA damage sites. Science 316(5828): 1198-202, 2007 Notes: *co-corresponding authors. Comment in: Cell signaling. A touching response to damage. Science. 2007 May 25;316(5828):1138-9; and in DNA repair: The big and the small picture Nature Reviews Molecular Cell Biology 8, 517-517

Messick TE, Greenberg RA: The ubiquitin landscape at DNA double-strand breaks. The Journal of Cell Biology 187(3): 319-26, 2009.

Patterson-Fortin J, Messick TE, Shao G, Bretscher H, and Greenberg RA. : Differential regulation of JAMM domain deubiquitinating enzyme activity within the RAP80 complex. J Biol Chem 285: 30971-81, 2010.

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Last updated: 12/08/2014
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