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Study of synthetic lethality in HPV-transformed cells

Grant number: 12/16512-8
Support Opportunities:Scholarships in Brazil - Doctorate (Direct)
Effective date (Start): September 01, 2012
Effective date (End): August 31, 2016
Field of knowledge:Biological Sciences - Biochemistry - Molecular Biology
Principal Investigator:Enrique Mario Boccardo Pierulivo
Grantee:Walason da Silva Abjaude
Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:10/20002-0 - Study of Synthetic Lethality in cells infected with Human Papillomaviruses (HPV), AP.JP


Persistent infection with high-oncogenic risk human papillomavirus (types) is etiologically associated almost all cervical cancer cases and with more than 50% of other anogenital malignant tumors. Infection with these viruses has been associated with genomic instability, a hallmark of most human cancers. High-risk HPV types express two oncoproteins, E6 and E7 that act on specific cellular factors promoting cell proliferation. These proteins are capable of inducing numeric and structural chromosomal alterations. Furthermore, they can modulate the cell response to DNA damage. Synthetic lethality describes a cellular condition where two (or more) non-allelic non-essential mutations, which do not cause cell death when expressed individually, are lethal when expressed together in the same cell. Cells transformed with high-risk HPV types constitute an interesting model for the study of synthetic lethality since E6 and E7 oncoproteins affect several signal transduction pathways such as those regulated by p53 and pRb, respectively. In the present study we will analyze the viability of HPV16 and HPV18 transformed cell lines (SiHa, CasKi, HeLa) upon systematic inhibition of genes involved in DNA damage repair or tumor suppressor genes. For this purpose we will use lentiviral libraries expressing specific shRNAs. Besides, we will study the effect of drugs that inhibit the different DNA damage repair systems or that cause DNA damage on these cell lines. The results will be validated in epithelial organotypic cultures expressing different viral genes to determine the involvement of the different HPV oncoproteins. Our approach may contribute to the identification of genes that are essential for HPV-transformed cell survival and to the development of new therapeutic strategies for the treatment of HPV-associated lesions. (AU)

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
ABJAUDE, WALASON; PRATI, BRUNA; MUNFORD, VERIDIANA; MONTENEGRO, ALINE; LINO, VANESCA; HERBSTER, SUELLEN; RABACHINI, TATIANA; TERMINI, LARA; MENCK, CARLOS FREDERICO MARTINS; BOCCARDO, ENRIQUE. ATM Pathway Is Essential for HPV-Positive Human Cervical Cancer-Derived Cell Lines Viability and Proliferation. PATHOGENS, v. 11, n. 6, p. 19-pg., . (17/02997-3, 13/27006-9, 12/16512-8, 10/20002-0, 19/19435-3)
PRATI, BRUNA; ABJAUDE, WALASON DA SILVA; TERMINI, LARA; MORALE, MIRIAN; HERBSTER, SUELLEN; LONGATTO-FILHO, ADHEMAR; LIMA NUNES, RAFAELLA ALMEIDA; CORDOBA CAMACHO, LIZETH CAROLINA; RABELO-SANTOS, SILVIA HELENA; ZEFERINO, LUIZ CARLOS; et al. Three Prime Repair Exonuclease 1 (TREX1) expression correlates with cervical cancer cells growth in vitro and disease progression in vivo. SCIENTIFIC REPORTS, v. 9, . (08/57889-1, 10/20002-0, 13/27006-9, 12/16512-8, 11/14416-9)
Academic Publications
(References retrieved automatically from State of São Paulo Research Institutions)
ABJAUDE, Walason da Silva. Study of synthetic lethality in HPV-transformed cells.. 2016. Doctoral Thesis - Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI) São Paulo.

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