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The role of hnRNP H in the splicing response to genotoxic stress

Stein, Chad (2015) The role of hnRNP H in the splicing response to genotoxic stress. Undergraduate Thesis, University of Pittsburgh. (Unpublished)

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Abstract

Since early in evolutionary history, alternative RNA splicing has been an important method for metazoan organisms to regulate gene expression, allowing for a vastly expanded proteome without the need for significant genome expansion. By tightly regulating the inclusion and exclusion of parts of genes using cis-acting elements and trans-acting factors, the splicing machinery can create specific isoforms of proteins in response to changes in developmental time, spatiotemporal or environmental factors, etc. Recently, misregulation of this system has been discovered increasingly in various disease states, including many (if not most) cancers. Significantly, aberrant alternative RNA splicing has been implicated in the acquisition of chemotherapy resistance to certain drugs, including cisplatin. Understanding how the splicing machinery fails to act properly in cancer will be important for creating novel gene-based therapies in the future. In this study, I aimed to understand how an important splicing factor implicated in the regulation of cancer-related transcripts, hnRNP H, causes changes in alternative splicing in its own mRNA and of other genes. It was shown that cisplatin causes a dose-dependent decrease in two paralagous exons, HNRNPH1 Exon 4 and HNRNPH3 Exon 3. Structurally similar control compounds did not cause such changes, implying that the effect is specific to cisplatin-induced genotoxic stress. Gel shift assays confirmed the interaction of hnRNP H with its own mRNA in these autoregulatory exons, implying a pathway that allows cancer cells to modulate the levels of this important protein factor.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Stein, Chadchadbstein@gmail.com
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairGrabowski, Paulapag4@pitt.eduPAG4
Committee MemberMilcarek, Christinemilcarek@pitt.eduMILCAREK
Committee MemberPolinko, Ericepolinko@pitt.eduEPOLINKO
Committee MemberLynch, Kristenklync@mail.med.upenn.edu
Date: 27 April 2015
Date Type: Publication
Defense Date: 26 March 2015
Approval Date: 27 April 2015
Submission Date: 16 April 2015
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 45
Institution: University of Pittsburgh
Schools and Programs: University Honors College
Degree: BPhil - Bachelor of Philosophy
Thesis Type: Undergraduate Thesis
Refereed: Yes
Uncontrolled Keywords: alternative RNA splicing, hnRNP H, genotoxic stress
Date Deposited: 27 Apr 2015 14:18
Last Modified: 15 Nov 2016 14:27
URI: http://d-scholarship.pitt.edu/id/eprint/24939

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