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Frida E. Kleiman, Ph.D.

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Professor - Biochemistry, Cell Biology, Molecular Biology

 frida

Director at Hunter of Support of Competitive Research (SCORE) Program, NIH

Biochemistry Program Coordinator, Graduate Center, City University of New York 

Contact Information:

Office/lab: Belfer building room 462 (tel 212-896-0451),  dept fax 212-772-5332, email fkleiman@hunter.cuny.edu

Education:

M.S.:National University of Córdoba, Argentina. Ph.D.: National University of Córdoba, Argentina. Postdoc: Columbia University.

Research Summary: 

The projects in our lab are aimed to study control of gene expression in different cellular conditions. The current view is that gene expression in different conditions and cell types is mainly regulated at the transcriptional and post-translational levels. Our research seeks to change this paradigm and aims to understand how cell-specific profiles are generated from mRNA 3’ processing and mRNA stability regulation. We study the effect of RNA binding proteins on mRNA profiles in different cellular conditions such as apoptosis, DNA damage response (DDR), aging, Alzheimer’s disease (AD), cancer, etc. We have shown that the dynamic macromolecular assembly of the RNA binding proteins, miRNA, mRNA 3′ processing machinery and factors involved in DDR and tumor suppression results in cell-specific 3′ processing profiles and transcriptome. Understanding the mechanisms and consequences of 3’ end regulation/mRNA stability in DDR constitutes a major challenge in this growing, but mainly, unexplored field. Our lab is interested in identifying and analyzing those protein complexes, to understand the molecular basis of the transcription-coupled RNA processing process and how these interactions regulate gene expression after DNA damage. These studies involve a large number of experimental approaches, including a variety of in vitro assays, cell imaging, biochemical fractionation and protein purification, cDNA and genomic DNA cloning, production of recombinant proteins and antibodies, and genetic analyses of cultured cells. 

Current projects in the lab include: 

Studies on the functional connections between mRNA 3’ end processing, tumor suppression and the DNA damage response. These studies are focused on the functional connections between mRNA 3’ end processing, tumor suppression and the DNA damage response. These studies have changed the paradigm that tumor suppressors control gene expression only in transcriptional and post-translational processes. Our studies showed that tumor suppressors can also regulate mRNA processing and mRNA stability. Our studies have shown that the dynamic macromolecular assembly of the mRNA 3′ processing machinery and factors involved in the DNA damage response and tumor suppression, such as BARD1/BRCA1 and p53, affect the amount and quality of target mRNAs. Our results showed that control of mRNA processing is also part of DNA damage response by avoiding the formation of shorter wrongly processed mRNAs and hence deleterious proteins. Currently, our studies are aimed to elucidate the molecular mechanism by which the mRNA processing factor CstF-50 regulates the BRCA1/BARD1-mediated ubiquitination pathway and the effect of this ubiquitination complex on cellular functions during DNA damage response. Although it is known that the tumor suppressors BRCA1/BARD1 exhibit Ub ligase activity, the mechanisms and cellular consequences of this function are not well understood. This project seeks to evaluate a new mechanism by which the binding of the mRNA processing factor CstF-50 to both BRCA1/BARD1 and its substrates helps in the assembly and/or stabilization of the ubiquitination complex during DNA damage response, resulting in the functional regulation of chromatin structure and gene expression. These studies will offer a better understanding of the role of BRCA1/BARD1-mediated ubiquitination pathway in the risk of tumor development and therapy success.

 Role of PARN deadenylase controlling mRNA steady-state levels during the DNA damage response. Our research is also aimed to understand role of poly(A)-specific ribonuclease (PARN) deadenylase controlling mRNA steady-state levels during the DNA damage response. Deadenylation is the first step in controlling mRNA stability and plays a key role in regulating gene expression. Almost all eukaryotic mRNAs are polyadenylated at the 3end, a default modification that confers stability to the mRNA. Deadenylation, which alters the length of poly(A) tails, is a highly regulated mechanism that results in changes in mRNA steady-state levels, transport, or translation initiation. Because deadenylation can regulate gene expression, it plays key roles in cellular responses, such as mRNA surveillance, DNA damage response, and tumor progression, as well as cell development and differentiation. Work from our lab showed a new level of control of a tumor suppressor expression by feedback loops in the p53 and mRNA 3’ processing pathways. They also showed for first time that PARN deadenylase plays an important role during DNA damage response controlling mRNA state-levels of genes involved in the response and resulting in cell-specific 3′ processing profiles. Studies from our lab have contributed to the studies of other groups in unrevealing the causes of Dyskeratosis congenita, an inherited, life-threatening bone marrow failure disorder.

Examination of how alternative polyadenylation (APA) events are involved in DDR. This a novel area for both the RNA processing and DNA damage response research fields. This project is aimed to study a new mechanism of control of gene expression during DNA damage response, which involves the selection of APA signals. The mechanism behind the use of APA signals is an ideal candidate to undergo regulation, promoting either cell survival or apoptosis. We propose to determine the mechanism(s) involved in the selection of polyadenylation signals during DNA damage response and the role(s) in regulating expression of genes involved in the response. Understanding the functional consequences of the usage of different polyadenylation signals will provide new insights on how control of gene expression upon DNA damage decides cellular fate, offering new opportunities for therapeutics.

 Determination of new mechanism(s) of tau-induced neurodegeneration. We propose that this might occur by nuclear functions of phosphorylated tau in regulating deadenylation, and hence gene expression, affecting the neuronal transcriptome before the appearance of traditional markers. This proposal is a logical continuation of prior work from my lab and it will allow the determination of new biological functions of tau, which might be responsible for the onset of the disease by controlling mRNA steady-state levels, hence gene expression, at different stages of the disease. 

 Determination of new mechanism(s) of tau-induced neurodegeneration. We propose that neurodegeneration might occur by nuclear functions of phosphorylated tau in regulating deadenylation, and hence gene expression, affecting the neuronal transcriptome before the appearance of traditional markers. These studies are a logical continuation of prior work from our lab and it will allow the determination of new biological functions of tau, which might be responsible for the onset of the disease by controlling mRNA steady-state levels, hence gene expression, at different stages of the disease. 

 Study of the role of RNA-binding protein in the DNA damage response. As most cellular processes involved post-transcriptional control of gene expression, enormous efforts to understand the role/s for RNA-binding proteins (RBPs) have evolved. Although HuR has been long recognized as an RBP that controls expression of genes involved in DDR and has been shown to be elevated in most aggressive breast cancers, how HuR function is controlled and the role of its ubiquitination and localization remains uncharacterized. We hypothesize that ubiquitination of HuR by the E3 Ub ligase BRCA1/BARD1 plays a role in regulating mRNA stability of genes involved in DNA damage response in different cellular conditions and in HuR translocation to cytoplasm, and that this phenomenon is regulated by other nuclear factors. Our studies will generate data with the potential to identify new RNA-targets of HuR during DNA damage response. 

Selected Publications

 Devany E, Park JY, Murphy MR, Zakusilo G, Baquero J, Zhang X, Hoque M, Tian B, Kleiman FE. (2016). Intronic cleavage and polyadenylation regulates gene expression during DNA damage response through U1 snRNA. Cell Discov. 2:16013. 

 Zhang X, Devany E, Murphy MR, Glazman G, Persaud M, Kleiman FE. (2015). PARN deadenylase is involved in miRNA-dependent degradation of TP53 mRNA in mammalian cells. Nucleic Acids Res. 43(22):10925-38. 

Zhang, X., Kleiman, F.E., and Devany, E. (2014). Deadenylation and its regulation in eukaryotic cells. Invitation to write chapter to a volume of the series "Polyadenylation: Methods and Protocols" in Methods in Molecular Biology, Humana Press. 1125:289-96. 

Devany, E., Zhang, X., Park, J.Y., Tian, B., Kleiman, F.E. (2013). Positive and negative feedback loops in the p53 and mRNA 3' processing pathways. Proc. Natl. Acad. Sci. USA 110: 3351-3356.

Goss, D.J., Kleiman, F.E. (2013).· Poly(A) Binding Proteins-Are they all created equal? Advance review in Wiley Interdisciplinary Reviews WIREs RNA. Mar;4(2):167-79.

Nazeer, F.I., Devany E., Mohammed, S., Fonseca, D., Akukwe, B., Taveras, C., and Kleiman, F.E. (2011). p53 inhibits mRNA 3' processing through its interaction with the CstF/BARD1 complex. Oncogene, 30(27):3073-83.

Zhang, X., Virtanen, A., and Kleiman, F.E. (2010). To polyadenylate, or to deadenylate: that is the question. Cell Cycle; 9(22):4437-4449.

Cevher, M.A., Zhang, X., Fernandez, S., Kim, S., Baquero, J., Nilsson, P., Lee, S., Virtanen, A., and Kleiman F.E. (2010). Nuclear deadenylation/polyadenylation factors regulate 3' processing in response to DNA damage. EMBO J. 29(10):1674-1687.

Cevher, M.A. and Kleiman, F.E. (2010). Connections between 3' end processing and DNA damage response. Focus article in Wiley Interdisciplinary Reviews WIREs RNA.http://wires.wiley.com/WileyCDA/WiresArticle/wisId-WRNA20.html

Mirkin, N., Fonseca, D., Mohammed, S., Cevher, M.A., Manley, J.L. and Kleiman, F.E. (2008). The 3' processing factor CstF functions in the transcription-coupled repair response. Nucleic Acids Research, 36(6):1792-1804.

Kim, H.S., Li, H., Cevher, M., Parmelee, A., Fonseca, D., Kleiman, F.E. and Lee, S.B. (2006). DNA damage-induced BARD1 phosphorylation is critical for the function of BRCA1/BARD1 complex. Cancer Res. 66(9):4561-4565.

Kleiman, F.E., Wu-Baer, F., Fonseca, D., Kaneko, S., Baer, R and Manley, J.L. (2005). BRCA1/BARD1 inhibition of 3’ processing involves targeted degradation of RNA polymerase II. Genes Dev. 15(10):1227-37.

Chen, A., Kleiman, F.E., Manley, J.L., Ouchi, T., and Pan, Z.Q. (2002). Auto-ubiquitination of the BRCA1/BARD1 RING ubiquitin ligase. J. Biological Chemistry, 277(24):22085-92.

Kleiman, F.E. and Manley, J.L. (2001). The BARD1-CstF-50 interaction links mRNA 3’ end formation to DNA damage and tumor suppression. Cell, 104:743-753.

Kleiman, F.E. and Manley, J.L. (1999). Functional interaction of BRCA1-associated BARD1 with polyadenylation factor CstF-50. Science, 285:1576-1579.