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Insights into the functional differences of the LARP1 DM15 region imparted by the cancer associated R824W mutation

Sosa, Jahree A (2022) Insights into the functional differences of the LARP1 DM15 region imparted by the cancer associated R824W mutation. Master's Thesis, University of Pittsburgh. (Unpublished)

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Eukaryotic cells must exert pointed control over gene expression processes to quickly respond to the extracellular environment. RNA binding proteins (RBPs) recognize and interact with class-defining sequences in mRNAs to regulate their translation. TOP mRNAs, a class of eukaryotic mRNAs that encode ribosomal proteins, are defined by a 5’UTRs motif containing an invariant +1C and 4-15nt pyrimidine tract adjacent to the 5’ cap. Proteins encoded by these mRNAs are essential for normal cell growth and are often overproduced in metastasizing cancer cells. TOP transcript regulation has been linked to the RBP La-related protein 1 (LARP1), whose overexpression is also associated with metastatic epithelial cancers and poorer prognosis. LARP1 is comprised of three RNA-binding domains, the La motif, the RNA-recognition motif, and the LARP1-specific DM15 motif. LARP1 regulation of TOP mRNAs is thought to mechanistically occur through the DM15 domain directly binding the 5’m7G cap and first few nucleotides of the TOP motif.
Molecular dynamics simulations of the LARP1 DM15 uncovered an allosteric connection between two residues on opposite faces of the domain: residues R847 and R824. DM15 R847 participates in hydrogen bonding interactions with the +1 nucleotide of a bound mRNA. R824 resides on the ‘back’ surface of DM15, far from the RNA-binding surface, yet facilitating putative interactions with other molecules. Interestingly, three COSMIC Cancer Database entries list identical LARP1 mutations at position 824 in breast cancer tissues, R824W. These data led us to hypothesize that R824 influences the RNA binding function of the LARP1 DM15 domain through its allosteric connection with R847.
This thesis set out to characterize the biochemical impacts of cancer-associated mutation R824W on the RNA-binding profile of the LARP1 DM15. The data reported suggest R824 plays significant roles in maintaining DM15 domain stability and RNA-binding affinity through modulating off-rate binding kinetics. Contextualizing our findings within the greater TOP mRNA regulatory pathways in cancer, we hypothesize a poorer functioning LARP1 R824W confers a growth advantage to cancer cells by weakening DM15 domain interactions with TOP mRNAs. Dampening LARP1 RNA binding affinity would allow TOP mRNA translation to continue unfettered by LARP1, thereby increasing cancer cell protein output.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Sosa, Jahree Ajas607@pitt.edujas607
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorBERMAN, ANDREA Jajb190@pitt.eduajb190
Date: 15 July 2022
Date Type: Publication
Defense Date: 29 March 2022
Approval Date: 15 July 2022
Submission Date: 7 April 2022
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 80
Institution: University of Pittsburgh
Schools and Programs: Dietrich School of Arts and Sciences > Biological Sciences
Degree: MS - Master of Science
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords: LARP, LARP1, LA-RELATED PROTEIN 1
Date Deposited: 15 Jul 2022 20:00
Last Modified: 15 Jul 2022 20:00

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  • Insights into the functional differences of the LARP1 DM15 region imparted by the cancer associated R824W mutation. (deposited 15 Jul 2022 20:00) [Currently Displayed]


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