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Title page for ETD etd-02082018-150116


Type of Document Dissertation
Author Martin, William Jay
URN etd-02082018-150116
Title RNA Recognition by the Histone Demethylase LSD1 and Proteinaceous RNase P: Characterization of the Binding of Highly Structured RNAs by Enzyme Complexes
Degree PhD
Department Biochemistry
Advisory Committee
Advisor Name Title
Neil Osheroff Committee Chair
David Cortez Committee Member
Gregor Neuert Committee Member
Martin Egli Committee Member
Nicholas Reiter Committee Member
Keywords
  • LSD1
  • RNA structure
  • TERRA
  • PRORP
  • SWIRM domain
  • PAR-CLIP
  • G-quadruplex
Date of Defense 2017-12-15
Availability restricted
Abstract
This study investigates the recognition of structured RNAs by two essential enzymes, proteinaceous RNase P (PRORP) and lysine-specific demethylase-1 (LSD1). PRORP binds and cleaves human mitochondrial precursor tRNAs in a fundamental step for the generation of mature mitochondrial transcripts. The enzyme recognizes specific structured domains of the pre-tRNAs in a manner similar to but distinct from the unrelated nuclear RNase P complex. In order to move towards a crystal structure of the PRORP-RNA complex, minimal constructs were generated and biochemically validated with binding studies and in vitro activity assays and used in crystallization studies.

LSD1 modulates gene expression through enzymatic histone demethylation and also serves as a protein scaffold in various large protein complexes. The long noncoding RNA (lncRNA) telomeric repeat-containing RNA (TERRA) has previously been demonstrated to recruit LSD1 to deprotected telomeres where it promotes the recruitment of the nuclease MRE11. Here, it is shown that LSD1 specifically recognizes the G-quadruplex structure formed by TERRA and other RNAs and a G-quadruplex RNA binding region is identified in the regulatory SWIRM domain of LSD1. Together, these studies advance our understanding of the role of structured RNAs in RNA/protein interactions.

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