Ales Vancura

Professor

St. John's College of Liberal Arts and Sciences

Ph.D.

Laboratory of Epigenetics

Research Overview

Our goal is to understand how cells alter their transcription profile and adapt to genotoxic stress, i. e., exogenous and endogenous factors that cause damage to cellular DNA. This is important, because DNA damage may lead to a number of different diseases including cancer. Since maintenance of genome integrity is crucial for survival, cells have evolved a set of highly conserved mechanisms to sense and signal damaged DNA; these mechanisms are collectively referred to as the DNA damage response (DDR). The work in our laboratory is currently focused on understanding the complex and multifaceted relationship between DDR, transcription, epigenetics, and chromatin. Defects in DDR-triggered transcription reprogramming compromise genome integrity, thus increasing predisposition to numerous cancers, premature aging, and other “genome instability” diseases. A better understanding of the relationship between DDR and transcription will contribute to the identification of novel targets and approaches for cancer treatment. Our work utilizes yeast and mammalian cell cultures and techniques of molecular and cell biology, biochemistry and genetics.

The work in this Laboratory has been significantly enhanced by the diligent and creative work of our students, who after graduating assumed positions at premier institutions (Rockefeller University, Harvard Medical School, Columbia Medical School, Brown University, New York University, and the National Institutes of Health).

The results of our research have been published in over 60 research articles and funded by the American Cancer Society and National Institutes of Health.

Funding

2023-2026 NIH grant R15GM151681

2020-2023 NIH grant R15GM135839

2016-2020 NIH grant R15GM120710

2013-2016 NIH grant R15 GM106324

2009-2013 NIH grant R15 GM08767

2006-2009 NIH grant R15 GM076075

2001-2005 American Cancer Society grant RSG01-145-01-CCG

1997-2001 NIH grant R15 GM55937

1995-1999 American Cancer Society grant BE-239

https://www.ncbi.nlm.nih.gov/sites/myncbi/1V3hp5faluEAa/bibliography/46399086/public/?sort=date&direction=descending

Selected Publications (from 2010)

Kaur, P., Nagar, S., Mehta, R., Sahadeo, K., Vancura, A. 2023. Hydroxyurea and inactivation of checkpoint kinase MEC1 inhibit transcription termination and pre-mRNA cleavage at polyadenylation sites in budding yeast. Scientific Reports 13: 13106.

Nagar, S., Mehta, R., Kaur, P., Liliah, R.T., Vancura, A. 2023. Tolerance to replication stress requires Dun1p kinase and activation of the electron transport chain. Biochim. Biophys. Acta – Mol. Cell. Res. 1870: 119382.

Kaur, P., Nagar, S., Bhagwat, M., Uddin, M., Zhu, Y., Vancurova, I., Vancura, A. 2021. Activated heme synthesis regulates glycolysis and oxidative metabolism in breast and ovarian cancer cells. PLoS One 16: e0260400.

Bhagwat, M., Naga,r S., Kaur, P., Mehta, R., Vancurova, I., Vancura, A. 2021. Replication stress inhibits synthesis of histone mRNAs in yeast by removing Spt10p and Spt21p from the histone promoters. J. Biol. Chem. 297: 101246.

Bhagwat M, Nagar S, Kaur P, Jassar S, Vancurova I, Vancura A. 2021. Synthesis of nucleocytosolic acetyl-CoA regulates mitochondrial respiration and ATP synthesis. Biochim. Biophys. Acta Mol. Cell. Res. 1868: 119025.

Kaur, P., Nagar, S., Bhagwat, M., Uddin, M.M., Zhu Y, Vancura A. 2020. Probing Metabolic Changes in IFN γ-Treated Ovarian Cancer Cells. Methods Mol Biol. 2108: 197-207.

Bu, P., Nagar, S., Bhagwat, M., Kaur, P., Shah, A., Zeng, J., Vancurova, I., Vancura, A. 2019. DNA damage response activates respiration and thereby enlarges dNTP pools to promote cell survival in budding yeast. J. Biol. Chem. 294: 9771-9786.

Vancurova, I., Uddin, M.M., Zou, Y., Vancura, A. 2018. Combination Therapies Targeting HDAC and IKK in Solid Tumors. Trends Pharmacol. Sci. 39:295-306.

Vancura, A., Bu, P., Bhagwat, M., Zeng, J., Vancurova, I. 2018. Metformin as an Anticancer Agent. Trends Pharmacol. Sci. 39:867-878.

Zou, Y., Uddin, M.M., Padmanabhan, S., Zhu, Y., Bu, P., Vancura, A., Vancurova I. 2018. The proto-oncogene Bcl3 induces immune checkpoint PD-L1 expression, mediating proliferation of ovarian cancer cells. J. Biol. Chem. 293: 15483-15496.

Vancura, A., Nagar, S., Kaur, P., Bu, P., Bhagwat, M., Vancurova, I. 2018. Reciprocal Regulation of AMPK/SNF1 and Protein Acetylation. Int. J. Mol. Sci. 19: 11.

Zhang, T., Galdieri, L., Hasek, J., Vancura, A. 2017. Yeast phospholipase C is required for stability of casein kinase I Yck2p and expression of hexose transporters. FEMS Microbiol. Lett. 364: 22. Vancura, A., Vancurova, I. 2017. Metformin induces protein acetylation in cancer cells. Oncotarget 8: 39939-39940.

Vancurova, I., Gatla, H.R., Vancura, A. 2017. HDAC/IKK inhibition therapies in solid tumors. Oncotarget 8:34030-34031.

Zhang, T., Bu, P., Zeng, J., Vancura, A. 2017. Increased heme synthesis in yeast induces a metabolic switch from fermentation to respiration even under conditions of glucose repression. J. Biol. Chem. 292:16942-16954.

Gatla, H.R., Zou, Y., Uddin, M.M., Singha, B., Bu, P., Vancura, A., Vancurova, I. 2017. Histone Deacetylase (HDAC) Inhibition Induces IκB Kinase (IKK)-dependent Interleukin-8/CXCL8 Expression in Ovarian Cancer Cells. J. Biol. Chem. 292: 5043-5054.

Galdieri, L., Zhang, T., Rogerson, D., Vancura, A. 2016. Reduced histone expression or a defect in chromatin assembly induces respiration. Mol. Cell. Biol. 36: 1064-1077.

Galdieri, L., Gatla, H., Vancurova, I., Vancura, A. 2016. Activation of AMP-activated protein kinase by metformin induces protein acetylation in prostate and ovarian cancer cells. J. Biol. Chem. 291: 25154-25166.

Singha, B., Gatla, H.R., Manna, S., Chang, T.-P., Sanacora, S., Poltoratsky, V., Vancura, A., Vancurova, I. 2014. Proteasome inhibition increases recruitment of IkB kinase b (IKKb), S536P-p65, and transcription factor EGR1 to interleukin-8 (IL-8) promoter, resulting in increased IL-8 production in ovarian cancer cells. J. Biol. Chem. 289: 2687-2700.

Mehrotra, S., Galdieri, L., Zhang, T., Zhang, M., Pemberton, L.F., Vancura, A. 2014. Histone hypoacetylation-activated genes are repressed by acetyl-CoA- and chromatin-mediated mechanism. Biochim. Biophys. Acta 1839: 751-763.

Galdieri, L., Zhang, T., Rogerson, D., Lleshi, R., Vancura, A. 2014. Protein acetylation and acetyl-coenzyme A metabolism in budding yeast. Eukaryot Cell 13: 1472-1483.

Galdieri, L., Chang, J., Mehrotra, S., Vancura, A. 2013. Yeast phospholipase C is required for normal acetyl-CoA homeostasis and global histone acetylation. J. Biol. Chem. 288: 27986-27998.

Zhang, M., Galdieri, L., Vancura, A. 2013. The yeast AMPK homolog SNF1 regulates acetyl-CoA homeostasis and histone acetylation. Mol. Cell. Biol. 33: 4701-4717. Selected for Spotlight section of Mol. Cell. Biol.

Galdieri, L., Vancura, A. 2012. Acetyl-CoA carboxylase regulates global histone acetylation. J. Biol. Chem. 287: 23865-23876. Selected as “JBC Best of 2012” and “Faculty 1000 Recommended”.

Galdieri, L., Moon, J., Vancura, A. 2012. Determination of histone acetylation status by chromatin immunoprecipitation. Methods Mol. Biol. 809: 255-65.

Chang, J., Vancura, A. 2012. Analysis of SUC2 promoter structure by nucleosome scanning. Methods Mol Biol 809: 321-33.

Galdieri, L., Desai, P., Vancura, A. 2012. Facilitated assembly of the preinitiation complex by separated tail and head/middle modules of the mediator. J. Mol. Biol. 415: 464-74.

Galdieri, L., Mehrotra, S., Yu, S., and Vancura, A. 2010. Transcriptional regulation in yeast during diauxic shift and stationary phase. OMICS 14: 629-638.

· Shreya Nagar, PhD, Postdoctoral Fellow, University of Chicago Medical School

· Pritpal Kaur, PhD, Postdoctoral Fellow, Johns Hopkins University Medical School

· Madhura Bhagwat, PhD, Research scientist, Eurofins Scientific

· Tiantian Zhang, PhD, Postdoctoral Fellow, Cornell University Medical School

· Man Zhang, PhD, Postdoctoral Fellow, Genentech

· Luciano Galdieri, PhD, Postdoctoral Fellow, Washington University Medical School

· Jennifer Chang, PhD, Postdoctoral Fellow, New York University Medical School

· Nilanjan Guha, PhD, Postdoctoral Fellow, Harvard University Medical School

· Parima Desai, PhD, Postdoctoral Fellow, University of Massachusetts Medical School

· Hongyu Lin, PhD, Postdoctoral Fellow, Rockefeller University (laboratory of Dr. Greengard, Nobel price laureate 2000)

· Jae Choi, PhD, Postdoctoral Fellow, National Institutes of Health

· Joey Zeng, DDM, Harvard Dental School

· Daniella Rogerson, MD, Columbia University Medical School

· John Moon, MD, SUNY Downstate Medical School

· Victoria Ruiz, PhD, Brown University