Roger A. Greenberg, MD, PhD

faculty photo
J. Samuel Staub, M.D. Professor
Department: Cancer Biology

Contact information
Department of Cancer Biology
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.
M.D.
Albert Einstein College of Medicine, 2000.
Ph.D. (Microbiology and Immunology)
Albert Einstein College of Medicine, 2000.
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Description of Research Expertise

Research Interests
This laboratory is devoted to understanding basic mechanisms of DNA repair and their impact on genome integrity, cancer etiology and response to targeted therapies. To investigate these interrelationships, we are devoted to elucidating BRCA1- and BRCA2- dependent homologous recombination mechanisms in breast and ovarian cancer, telomere length maintenance mechanisms that rely on a specialized form of homologous recombination, and DNA damage induced activation of immune responses to cancer. 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, DNA repair, Homologous Recombination, Telomeres, Epigenetics, Breast Cancer, Ovarian Cancer, cytokines, immune therapy.

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.

Greenberg Lab Website
Learn more about the lab's research here.


Lab personnel:
Weihua Li - Research Specialist, Lab Manager
Moniher Deb - Research Specialist, Penn Center for Genome Integrity
Lei Tian - Research Associate
Jie Chen - Postdoctoral Researcher
Eva Hum - Postdoctoral Researcher
Vidhya Krishnamoorthy - Postdoctoral Researcher
Tim Lippert - Postdoctoral Researcher
Yaroslav Morozov - Postdoctoral Researcher
Roxanne Oshidari - Postdoctoral Researcher
Jenny Stundon - Postdoctoral Fellow
Priyanka Verma - Postdoctoral Researcher
Xuejiao Yang - Postdoctoral Researcher
Tianpeng Zhang - Postdoctoral Researcher
Yiwen Li – Undergraduate Student
Angela Wu - Undergraduate Student



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

Selected Publications

Chen J, Harding SM, Natesan R, Tian L, Benci JL, Li W, Minn AJ, Asangani I, and Greenberg RA. : Cell cycle checkpoints cooperate to suppress DNA and RNA associated molecular pattern recognition and anti-tumor immune responses. Cell Reports 32(1): 1-15, September 2020.

Verma P, Dilley RL, Zhang T, Gyparakai MT, Li Y, and Greenberg RA: RAD52 and SLX4 act non-epistatically to ensure telomere stability during alternative telomere lengthening. Genes & Development 33: 221-235, Feb 2019.

Walden M*, Tian L*, Ross R, Sykora UM, Byrne DP, Hesketh EL, Masandi SK, Cassel J, Geirge R, Ault JR, Oualid FE, Pawlowski K, Salvino JM, Eyers PA, Ranson NA, Del Galdo F, Greenberg RA#, Zeqiraj E#: Metabolic control of BRISC-SHMT2 assembly regulates immune signaling. Nature 10.1038/s41586-019-1232-1, May 2019 Notes: * Co-first authors # co-corresponding authors.

Greenberg RA: Assembling a protective shield. Nature Cell Biology 8: 862-863, July 2018.

Li ML, Jiang Q, Bhanu NV, Wu J, Li W, Garcia BA, Greenberg RA.: Phosphorylation of TIP60 suppresses 53BP1 localization at DNA damage sites. Molecular and Cellular Biology [Epub ahead of print], October 2018.

Harding SM, Benci JL, Irianto J, Discher DE, Minn AJ, Greenberg RA: Mitotic progression following DNA damage enables pattern recognition within micronuclei. Nature 548: 466-470, August 2017.

Dilley RL, Verma P, Cho NW, Winters HD, Wondisford AR, and Greenberg RA: Break-Induced Telomere Synthesis Underlies Homology-Directed Telomere Maintenance. Nature 539(7627): 54-58, 2016 Notes: Comment in Nature: Telomere-lengthening mechanism revealed. Roake CM, Artandi SE. Nature. 2016 Oct 19. doi: 10.1038/nature19483.

Cho NW, Dilley RL, Lampson MA, Greenberg RA: Interchromosomal Homology Searches Drive Directional ALT Telomere Movement and Synapsis. Cell 159(1): 108-21, 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 5(2): 135-42, 2015.

Verma P, Greenberg RA: Noncanonical Views of Homology Directed DNA Repair. Genes & Development 30(10): 1138-54, 2016.

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.

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.

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, 2010.

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

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. Nature Structural & Molecular Biology 20(3): 317-25, 2013.

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 5(1): 180-93, 2013 Notes: # co-first author * co-corresponding author.

Cho NW, Greenberg RA: Familiar ends with alternative endings. Nature 518(7538), 2015.

Zeqiraj E, Tian L, Piggott CA, Pillon MC, Duffy NM, Ceccarelli DF, Keszei AF, Lorenzen K, Kurinov I, Orlicky S, Gish G, Heck AJR, Guarné A, Greenberg RA* and Sicheri F*: Higher order assembly of BRCC36–KIAA0157 is required for DUB activity and biological function. Molecular Cell 59(6): 970-83, 2015 Notes: *co-corresponding authorship.

Jiang Q, Paramasivam M, Aressy B, Wu J, Bellani M, Tong W, Seidman MM, Greenberg RA: MERIT40 cooperates with BRCA2 to resolve DNA inter-strand crosslinks. Genes & Development 29(18): 1955-68, 2015.

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Last updated: 12/27/2020
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