Function and regulation of PARP13 binding to cellular RNA
Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biology, 2015.
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| Format: | Thesis |
| Language: | eng |
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Massachusetts Institute of Technology
2015
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| Online Access: | http://hdl.handle.net/1721.1/97789 |
| _version_ | 1826194647361257472 |
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| author | Todorova, Tanya (Tanya Todorova) |
| author2 | Paul Chang. |
| author_facet | Paul Chang. Todorova, Tanya (Tanya Todorova) |
| author_sort | Todorova, Tanya (Tanya Todorova) |
| collection | MIT |
| description | Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biology, 2015. |
| first_indexed | 2024-09-23T09:59:12Z |
| format | Thesis |
| id | mit-1721.1/97789 |
| institution | Massachusetts Institute of Technology |
| language | eng |
| last_indexed | 2024-09-23T09:59:12Z |
| publishDate | 2015 |
| publisher | Massachusetts Institute of Technology |
| record_format | dspace |
| spelling | mit-1721.1/977892019-04-11T00:30:09Z Function and regulation of PARP13 binding to cellular RNA Todorova, Tanya (Tanya Todorova) Paul Chang. Massachusetts Institute of Technology. Department of Biology. Massachusetts Institute of Technology. Department of Biology. Biology. Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biology, 2015. Cataloged from PDF version of thesis. Vita. Includes bibliographical references. Poly(ADP-ribose) polymerase-13 (PARP13) is a member of the PARP family of proteins - enzymes that use NAD+ to synthesize a posttranslational protein modification called poly(ADP-ribose) (PAR). PARPs function in multiple cellular pathways, and recently several members of the family have been implicated in regulating various steps in RNA metabolism, from splicing to translation and decay. PARP1 3 is the best-understood RNA-regulatory PARP. Initially discovered as a host immune factor, PARP13 functions by binding viral transcripts via its four CCCH-type zinc fingers and targeting them for degradation. In the context of the immune response PARP1 3 can also inhibit the translation of its viral targets and enhance the activity of other RNA-binding viral receptors, such as RIG-1. More recently PARP13 was shown to also indirectly regulate the cellular transcriptome by inhibiting the activity of Argonaute 2 (Ago2), a member of the miRNA silencing pathway. While itself catalytically inactive, PARP13 is modified by PAR and can target Ago2 for modification by a yet unknown PARP. However, it remains unclear if RNA binding is required for this function of PARP1 3. Indeed, even though multiple viruses are known to be restricted by PARP13, cellular mRNA targets of PARP13 binding and regulation have not yet been identified. Here we show that PARP1 3 binds endogenous RNA and regulates the cellular transcriptome. We identify TRAILR4 mRNA as the first cellular target of PARP13 regulation and demonstrate that PARP13 represses TRAILR4 expression posttranscriptionally by binding to a specific region in the 3' untranslated region of the transcript and targeting it for degradation in a primarily 3'-5' decay mechanism. By inhibiting the expression of TRAILR4 - a decoy pro-survival receptor of the apoptotic ligand TRAIL, PARP1 3 regulates the cellular response to TRAIL and acts as a pro-apoptotic factor. We also examine possible mechanisms of regulation of PARP1 3 function. We identify the RNA-helicase DHX30 as a constitutive PARP1 3-interacting protein and show that the two proteins co-regulate a subset of cellular transcripts. We further demonstrate that the PAR-binding domain of PARP1 3 inhibits RNA binding, while PARP1 3 interaction with PARP5a and covalent modification with PAR appear to be mutually exclusive with RNA binding. by Tanya Todorova. Ph. D. 2015-07-17T19:46:42Z 2015-07-17T19:46:42Z 2015 2015 Thesis http://hdl.handle.net/1721.1/97789 911659296 eng M.I.T. theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. See provided URL for inquiries about permission. http://dspace.mit.edu/handle/1721.1/7582 171, 542-548 pages application/pdf Massachusetts Institute of Technology |
| spellingShingle | Biology. Todorova, Tanya (Tanya Todorova) Function and regulation of PARP13 binding to cellular RNA |
| title | Function and regulation of PARP13 binding to cellular RNA |
| title_full | Function and regulation of PARP13 binding to cellular RNA |
| title_fullStr | Function and regulation of PARP13 binding to cellular RNA |
| title_full_unstemmed | Function and regulation of PARP13 binding to cellular RNA |
| title_short | Function and regulation of PARP13 binding to cellular RNA |
| title_sort | function and regulation of parp13 binding to cellular rna |
| topic | Biology. |
| url | http://hdl.handle.net/1721.1/97789 |
| work_keys_str_mv | AT todorovatanyatanyatodorova functionandregulationofparp13bindingtocellularrna |