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 interested in identifying basic mechanisms involved in maintaining genome integrity and understanding their relationship to human malignancy. In particular, we are devoted to the elucidation of BRCA1-dependent signaling pathways necessary for appropriate repair of DNA double strand breaks and suppression of breast and ovarian cancer.

Key words: BRCA1, BRCA2, RAP80, BRCC36, MERIT40, Ubiquitin, ATM, DNA repair, chromatin, epigenetics, cellular senescence, Breast Cancer, Ovarian Cancer.

Description of Research
Description of Research

Germline mutation of either the Breast Cancer 1 (BRCA1) or Breast Cancer 2 (BRCA2) genes greatly predisposes individuals to breast and ovarian epithelial cancers. Clinical BRCA1 and BRCA2 mutations render cells deficient in DNA damage checkpoint signaling and error-free mechanisms of DNA repair known as homologous recombination, strongly supporting a role for these activities in tumor suppression.

Our research has contributed to the developing concept of a BRCA1-centered breast and ovarian tumor suppressor network. BRCA1 forms several distinct DNA damage inducible 'supercomplexes,' each dedicated to specific checkpoint and repair activities following genotoxic stress. These studies have provided a framework for understanding the in vivo consequences of mutations within the BRCA1 network (i.e. genes encoding BRCA1-interacting proteins) (Greenberg et al. Genes&Dev 2006). Recent work has revealed a partial molecular understanding for how BRCA1 recognizes DNA damage sites (Sobhian et al., Science 2007). 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 checkpoint and repair responses to ionizing radiation (Sobhian et al. Science 2007; Shao et al. Genes&Dev 2009; Shao et al. PNAS 2009; Nikkila et al. Oncogene 2009). Cancer causing BRCA1 BRCT mutants fail to interact with RAP80 and consequently demonstrate inefficient recruitment to DNA damage sites. Thus a series of ordered events involving ubiquitin recognition, breakdown and synthesis are required for BRCA1-dependent DNA damage responses. Future work will address the relationship between ubiquitin turnover and BRCA1-dependent DNA repair function. These studies should provide a detailed knowledge of the (1) molecular determinants required for BRCA1 recognition of DNA damage, and (2) how BRCA1 influences DNA repair mechanism specificity. Clinical mutations frequently disrupt these activities, thus understanding the basis for BRCA1 recognition of DNA damage should lend significant new insight into BRCA1 dependent DNA repair and tumor suppression mechanisms.

A second area of interest in the laboratory is the complex relationship between chromatin structure and DNA repair. We have recently developed novel systems to investigate interrelationships between chromatin structure and DNA double strand break (DSB) repair (Shanbhag et al. Cell 2010). Using these systems, we have shown that DSBs induce an ATM kinase dependent transcriptional silencing that spans multiple kilobases of chromatin in cis to the site of DNA damage. We intend to utilize these systems to reveal new insights into the interplay between chromatin structure and DNA repair, and how DNA repair responses influence diverse biological phenomena including cellular senescence and viral latency. We will also use these and related experimental systems to explore the molecular basis underlying epigenetic changes that occur during carcinogenesis.


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:
Vibhor Gupta - Postdoctoral Researcher
Laura Butler - Postdoctoral Researcher
Shane Harding - Postdoctoral Researcher
Lei Tian - Postdoctoral Researcher
Jingwen Zhang - Postdoctoral Researcher
Nam Woo Cho - Graduate Student
Nabil Sayed - Graduate Student
Qinqin Jiang - Graduate Student
Mischa Li - Graduate Student
Junmin Wu - Research Specialist

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

Selected Publications

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.

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.

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.

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.

Guzzo CM, Berndsen CE, Zhu J, Gupta V, Datta A, Greenberg RA, Wolberger C, Matunis MJ: RNF4-dependent hybrid SUMO-ubiquitin chains are signals for RAP80 and thereby mediate the recruitment of BRCA1 to sites of DNA damage. Sci Signal 5(253): ra88. doi: 10.1126, 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.

Nikkilä J, Coleman KA, Morrissey D, Pylkäs K, Erkko H, Messick TE, Karppinen S-M, Amelina A, Winqvist R*, Greenberg RA*: Familial breast cancer screening reveals an alteration in the RAP80 UIM domain that impairs DNA damage response function. Oncogene 28(16): 1843-52, 2009 Notes: *co-corresponding authors.

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.

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

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

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.

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Last updated: 02/27/2014
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