- The molecular basis of the transcription-coupled repair process and how these interactions regulate gene expression after DNA damage
- Ph.D., National University of Córdoba, Argentina
- M.S., National University of Córdoba, Argentina
- Postdoc, Columbia University
Dr. Frida Kleiman received a MS and PhD from the National University of Córdoba, Argentina. She did her postdoc at Columbia University. At Hunter College, she teaches courses in biochemistry. Her research focuses on molecular basis of the DNA damage response and its correlation with control of gene expression and cancer.
Areas of Expertise
The projects in our lab are aimed to study control of gene expression. 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), 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.
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 DDR. 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.
We show that the dynamic macromolecular assembly of the mRNA 3′ processing machinery and factors involved in the DDR and tumor suppression affect the amount and quality of target mRNAs. Role of PARN deadenylase controlling mRNA steady-state levels during the DDR. 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, DDR, and tumor progression. We showed for first time that PARN deadenylase plays an important role during DDR controlling mRNA state-levels of genes involved in the response and resulting in cell-specific 3′ processing profiles. 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 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 (RBPs) in the DDR. 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 DDR and in HuR translocation to cytoplasm. Examination of how alternative polyadenylation (APA) events are involved in DDR. This a novel area for both the RNA processing and DDR research fields. This project is aimed to study a new mechanism of control of gene expression during DDR, 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.
- 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. 43:10925-38.
- 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, Xiao S, Rameau RD, Devany E, Nadeem Z, Caglar E, Ng K, Kleiman FE, Saxena A. (2018). Nucleolin phosphorylation regulates PARN deadenylase activity during cellular stress response. RNA Biol. 15(2):251-260.
- Fonseca D, Baquero J, Murphy MR, Aruggoda G, Varriano S, Sapienza C, Mashadova O, Rahman S, Kleiman FE. (2018). mRNA Processing Factor CstF-50 and Ubiquitin Escort Factor p97 Are BRCA1/BARD1 Cofactors Involved in Chromatin Remodeling during the DNA Damage Response. Mol Cell Biol. 15;38(4).
- Alonso AD, Cohen LS, Corbo C, Morozova V, ElIdrissi A, Phillips G, Kleiman FE. (2018). Hyperphosphorylation of Tau Associates With Changes in Its Function Beyond Microtubule Stability. Front Cell Neurosci. 12:338.
- Baquero J, Varriano S, Ordonez M, Kuczaj P, Murphy MR, Aruggoda G, Morozova V, Makki AE, Alonso A, Kleiman FE (2019). Nuclear tau, p53 and Pin1 regulate PARN-mediated deadenylation and gene expression. Front Mol Neurosci. (doi: 10.3389/fnmol.2019.00242.).
- Murphy MR, Kleiman FE. (2019). Connections between 3′ end processing and DNA damage response: Ten years later. Wiley Interdiscip Rev RNA e1571. doi: 10.1002/wrna.1571. Review.