Gargi Ghosal, Ph.D.

Assistant Professor

Gargi Ghosal

Department of Genetics, Cell Biology and Anatomy

Indian Institute of Science, Bangalore, India (Ph.D.), 2007
Yale University, Newhaven, CT, 2009
University of Texas MD Anderson Cancer Center, Houston, TX, 2014
Baylor College of Medicine/ Texas Children’s Hospital, Houston, TX, 2016

Phone:402-559-5975 (Office)
Email: gargi.ghosal@unmc.edu

Honors and Awards
K22 Career Development Award, NCI, 2016-2019 

Currently recruiting Graduate students, Postdoctoral fellow and Research technician

Research Area: 

Replication stress response in Cancer and Premature Ageing

The research focus of the laboratory will be to examine the molecular basis of replication stress response in cancer and age-related disorders. Replication stress results due to slowing or stalling of the DNA replication machinery when it encounters, secondary DNA structures, DNA damage or due to factors that alter the levels of dNTP pool, proteins involved in DNA synthesis, hyper-DNA replication caused by the activation of origins and by oncogene overexpression. Stalled forks are deleterious, as unrepaired or misrepaired stalled forks lead to fork collapse resulting in cell death or chromosomal abnormalities leading to cancer, genetic disorders, ageing and diseases with cancer predisposition such as Werner syndrome, Bloom syndrome, Fanconi anemia, to name a few.

My interest in replication stress response arose during my research studies on identifying and characterizing key repair enzymes in DNA damage response (DDR). Previously, we have shown that the annealing helicase activity of both HARP and AH2 proteins are required for their function in preventing fork collapse and genomic instability. In addition, we identified and characterized the biochemical function of FAN1, FANCI-FANCD2 associated nuclease, in repairing DNA inter-strand crosslinks (ICLs). Further, we identified and characterized Spartan as a PCNA-interacting protein required for cell survival upon UV-induced DNA damage and a regulator of translesion DNA synthesis promoting survival and preventing genome instability. Cells respond to replication stress by activating the cell cycle checkpoint and recruit proteins that stabilize stalled forks and the DNA repair machinery to repair DNA damage before DNA replication ensues. Thus, replication stress response is an intricate network of well coordinated cascade of cellular events, the molecular mechanism of which is still being unraveled.

The area of research in the laboratory would be to understand the molecular mechanism of replication stress response upon DNA damage and oncogene induced replication stress with the focus on:

A) Roles of translesion DNA synthesis in replication stress and tumorigenesis. Translesion DNA synthesis (TLS) is a post-replication repair pathway, which mediates bypass of DNA lesions that stall replication forks, during DNA replication. Bypass of DNA lesions is mediated by specialized low-fidelity TLS polymerase that can replicate over distortions or bulky DNA adducts efficiently, leaving behind the lesion to be repaired at a later time point. Given that TLS polymerases do not have proofreading activities, engagement of this pathway would also result in the generation and accumulation of somatic mutations. Thus, it is not surprising that cancer cells may employ this pathway to bypass DNA lesions, arisen during hyper-proliferation and/or in response to radiation and other chemotherapeutic agents and evolve to become treatment resistant. We identified Spartan as a key regulator of TLS. Mutations in Spartan gene cause early onset hepatocellular carcinoma, genome instability and progeroid features. We will delineate the functions of Spartan and TLS in replication stress, genome instability and cancer.

B) Oncogene induced replication stress response in Ewing Sarcoma. EWS-FLI1 gene fusion causes Ewing sarcoma, second most common primary bone cancer affecting children. Deregulated expression of EWS-FLI1 transcriptional targets have shown to drive oncogenesis, but do not fully explain the disease phenotype. Additional roles of EWS-FLI1 in DDR and cell-cycle checkpoint is only beginning to unravel. We will delineate the roles of EWS and FLI1 in DDR upon replication stress and how these functions are altered by the expression of the pathological EWS-FLI fusion protein in Ewing sarcoma. The potential effects on sarcoma oncogenesis and drug resistance will be studied.

C) Replication stress response signaling and DNA repair. Identifying key enzymes and pathways that stabilize and repair stalled forks; study the regulatory mechanisms of replication stress response signaling and repair processes and; the cross-talk of cell-cycle checkpoint and DNA repair pathways that function to remove DNA lesions.

While replication stress can lead to development of cancer, on the other hand, inducing replication stress is the mode of action of most chemotherapeutic drugs used to kill cancer cells. These studies will help understand the basic science underlying replication stress response, identify new targets and biomarkers for cancer therapy and facilitate the development of strategies to overcome drug resistance and improve cancer therapy.

Publications listed in PubMed

Publications:

  1. Ghosal G and Yustein JT. EWS-FLI1 regulates genotoxic stress response in Ewing sarcoma. J of Cancer Biol and Res, J Cancer Biol Res, 3(2): 1063 May, 2015.
  2. Tian Y, Paramasivam M, Ghosal G, Chen D, Shen X, Huang Y, Akhter S, Legerski R, Chen J, Seidman MM, Qin J and Li L. UHRF1 Contributes to DNA Damage Repair as a Lesion Recognition Factor and Nuclease Scaffold. Cell Rep. 10(12):1957-66, Mar 31, 2015.
  3. Ghosal G and Chen J. DNA damage tolerance: a double-edged sword guarding the genome. Transl Cancer Res, 2(3): 107-129, June, 2013.
  4. Ghosal G, Lueng J, Nair B C, Will Fong, Chen J. PCNA-binding protein C1orf124 is a regulator of translesion synthesis. J Biol Chem, 287(34225-33), Aug 17, 2012.
  5. Yuan J#, Ghosal G#, Chen J. The HARP-like domain containing protein AH2 binds to PCNA and participate in cellular response to replication stress. Mol Cell. 47(3):410-21, Aug 2012 (# Co-first author)
  6. Ghosal G, Yuan J, Chen J*. The HARP domain dictates the annealing helicase activity of HARP/SMARCAL1. EMBO Rep. 12(6):574-80, Jun 2011.
  7. Liu T#, Ghosal G#, Yuan J, Huang J*, Chen J*. FAN1 acts with FANCDI-FANCD2 to promote DNA interstrand cross-link repair. Science. 329(5992):693-6, Aug 2010 (# Co-first author)
  8. Yuan J, Ghosal G, Chen J. The annealing helicase HARP protects stalled replication forks. Genes Dev. 23(20):2394-9, Oct 2009.
  9. Huang J, Gong Z, Ghosal G, Chen J. SOSS complexes participate in the maintenance of genomic stability. Mol Cell. 35(3):384-93, Aug 2009.
  10. Ghosal G, Muniyappa K. The characterization of Saccharamyces cerevisiae Mre11/Rad50/Xrs2 complex reveals that Rad50 negatively regulates Mre11 endonucleolytic but not the exonucleolytic activity. J Mol Biol.372(4):864-82, Sept 2007.
  11. Ghosal G, Muniyappa K. Saccharomyces cerevisiae Mre11 is a high-affinity G4 DNA-binding protein and a G-rich DNA-specific endonuclease: implications for replication of telomeric DNA. Nucleic Acids Res. 33(15):4692-703, Aug 2005.