Dr. Frida Kleiman

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. Coordinator of Hunter College Path to Success program (HCPSP) for the last five years to increase research competitiveness of faculty in under-resourced institutions with heavy demands on training and graduating students from underrepresented groups in biomedical research.

Educational background:

• National University of Córdoba, Argentina (MS 1989)
• National University of Córdoba, Argentina (PhD 1995)
• Columbia University (Postdoc. 2003)

Courses taught have included:

• CHEM 37800 Biochemistry Laboratory.
• CHEM 376 Biochemistry I.
• CHEM 377 Biochemistry II.

Research:

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 and animal models.

Our studies on the functional connections between mRNA 3' end processing, tumor suppression and the DDR 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. 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.

Extending those studies, we are exploring the possibility 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.

As mRNA steady-state levels are also regulated by RNA-binding proteins (RBPs), we also study how this mechanism is regulated during DRR. 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. Currently, our model is focused on a long-non coding RNA produced by APA in the CDKN1A gene, which codes for the tumor suppressor gene and global regulator of the cell-cycle p21.