Skip to Main Content
 

Global Search Box

 
 
 

ETD Abstract Container

Abstract Header

Identifying regulatory mechanisms for evolutionarily conserved StARkin domains of plant transcription factors and human tumor suppressors.

Holub, Ashton Skyler
http://orcid.org/0000-0002-9443-8358
http://rave.ohiolink.edu/etdc/view?acc_num=osu166980944747324

Abstract Details

2022, Doctor of Philosophy, Ohio State University, Molecular Genetics.
StARkin domains are a superfamily of structurally conserved ligand binding domains found in all the domains of life. These domains use a diverse set of mechanisms to regulate the activity of multidomain proteins they are integrated into, will identified roles in mediating homo/heteromeric interactions, subcellular localization, protein stability, and protein turnover. One subfamily of StARkin domains, StAR-related lipid transfer (START) domains, is found in both plant CLASS III HOMEODOMAIN-LEUCINE ZIPPER (HD-ZIPIII) transcription factors (TFs) and human deleted in liver cancer (DLC) tumor suppressor genes. Both families of proteins have critical roles in development, however, roles of the START domain in regulating the activity of either of these protein families is largely unknown. In Arabidopsis thaliana, phylogenetic analysis of HD-ZIPIII paralogs shows divergent activity stemming from coding sequence divergence, separating the five HD-ZIPIII paralogs into two sister clades, the REVOLUTA clade and the CORONA clade. HD-ZIPIII paralogs have redundant developmental activities, with distinct and antagonist effects between these sister clades. Preliminary work in our lab investigating the START domain of a representative REVOLUTA clade paralog, PHABULOSA (PHB), shows that the START domain is required for the developmental activity of PHB and regulates homodimerization, DNA-binding, and transactivation potential. In this study, I present the divergent activity of a representative CORONA clade paralog, CORONA (CNA), mediated by its START domain. We identify the target genes of PHB and CNA, highlighting overlapping, distinct, and antagonist regulation of target genes representative of their redundant developmental roles with distinct, and antagonist effects on each other. Additionally, using domain swap experiments, I identify two new properties of the CNA START domain in modulating the behavior of the binding sites of CNA, as well as modulating transactivation / transrepression activity. Together, these findings support a role of mutations to HD-ZIPIII START domains in driving the divergence of REVOLUTA and CORONA clade HD-ZIPIII paralogs. Human DLC family tumor suppressor genes are a family of StARkin domain containing RhoGTPase activating proteins (RhoGAPs). In cancers, DLC proteins are often downregulated or mutated, which is associated with poor prognosis in lung, liver, breast, and colon cancers. Using evolutionary analysis, we mine the Catalogue of Somatic Mutations in Cancer (COSMIC) database and identify mutations overrepresented in conserved residues of DLC START domains. Using structure-function analysis of homology models containing these mutations, we predict the consequences of these mutations in the tertiary structure of the START domains of these proteins. Broadly, this work investigating the START domains of plant HD-ZIPIII TFs and human DLC family tumor suppressors highlights the value of utilizing evolution and structure-function analysis to identify residues which contribute to the activity of a protein. Our work with the CNA START domain identifies it as tolerant to mutations, and we propose StARkin domains as flexible molecular tools utilized by evolution to drive the divergence of paralogous genes.
Aman Husbands (Advisor)
Jay Hollick (Committee Member)
Mark Seeger (Committee Member)
Ruben Petreaca (Committee Member)
Amanda Bird (Committee Member)
211 p.
Biology; Molecular Biology; Plant Biology
Development; transcription factors; HD-ZIPIII; Arabidopsis; Evolution; START Domains; Cancer; Deleted in Liver Cancer; ancestral sequence reconstruction;

Recommended Citations

Citations

  • Holub, A. S. (2022). Identifying regulatory mechanisms for evolutionarily conserved StARkin domains of plant transcription factors and human tumor suppressors. [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu166980944747324

    APA Style (7th edition)

  • Holub, Ashton. Identifying regulatory mechanisms for evolutionarily conserved StARkin domains of plant transcription factors and human tumor suppressors. 2022. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu166980944747324.

    MLA Style (8th edition)

  • Holub, Ashton. "Identifying regulatory mechanisms for evolutionarily conserved StARkin domains of plant transcription factors and human tumor suppressors." Doctoral dissertation, Ohio State University, 2022. http://rave.ohiolink.edu/etdc/view?acc_num=osu166980944747324

    Chicago Manual of Style (17th edition)

osu166980944747324
31
© 2022, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.