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Making Ends Meet: Role of the LARP1 La-Module in TOP mRNA Recognition

Al-Ashtal, Hiba (2020) Making Ends Meet: Role of the LARP1 La-Module in TOP mRNA Recognition. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

The La-related protein (LARP) superfamily is a diverse family of RNA-binding proteins that are characterized by an N-terminal La-Module. The La-Module is comprised of two RNA-binding domains, a La Motif (LAM) and an RNA recognition motif (RRM), which synergistically engage RNA. Sequence and structural changes to the La-Module lead to unique RNA binding specificity and biological function. For example, the La-Module of Genuine La, the prototypical LARP, binds the 3’UUU-OH of pre-tRNAs to facilitate their folding and maturation. In contrast, the LARP6 La-Module binds a stem-loop within the 5’UTR of collagen mRNAs to regulate their translation. LARP1 is the most divergent member of the LARP superfamily, and has been implicated in the stability and translation of mRNAs encoding the translation machinery.
The RNA binding partners and function of the LARP1 La-Module remain elusive. Because it associates with Poly(A)-binding protein, we hypothesized that the LARP1 La-Module has evolved to bind poly(A) RNA; we found that the La-Module indeed binds poly(A) RNA. Interestingly, we discovered that it simultaneously engages the 5’ terminal oligopyrimidine (TOP) motif characteristic of mRNAs that encode the translation machinery. We hypothesize that through binding to features at the 5’ and 3’ end of TOP mRNAs, the 5’ TOP motif and poly(A) tails, the La-Module may aid mRNA circularization to regulate TOP mRNA translation regulation. In addition, multivalent interactions between the La-Module and mRNAs may aid sequestration of TOP mRNAs to stress granules and processing-bodies during translation repression in response to stress.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Al-Ashtal, Hibahaa72@pitt.edu
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairBerman, Andreaajb190@pitt.edu
Committee MemberBrodsky, Jeffreyjbrodsky@pitt.edu
Committee MemberGrabowski, Paulapag4@pitt.edu
Committee MemberVanDemark, Andrewandyv@pitt.edu
Committee MemberNandakumar, Jayakrishnanjknanda@umich.edu
Date: 8 June 2020
Date Type: Publication
Defense Date: 2 March 2020
Approval Date: 8 June 2020
Submission Date: 18 March 2020
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 153
Institution: University of Pittsburgh
Schools and Programs: Dietrich School of Arts and Sciences > Biological Sciences
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: LARP1 TOP mRNA translation
Date Deposited: 08 Jun 2020 15:44
Last Modified: 08 Jun 2020 15:44
URI: http://d-scholarship.pitt.edu/id/eprint/38345

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