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SAMHD1: ORTHOGONAL REGULATION OF A MULTIFUNCTIONAL ENZYME

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abstract
SAMHD1 is multifunctional enzyme with dual roles in dNTP regulation and DNA repair. As a dNTP hydrolase (dNTPase), SAMHD1 is a key player in processes that rely on dNTPs including DNA synthesis and repair, cell cycle control, and innate immunity. In addition to this canonically recognized role as a dNTPase, SAMHD1 also binds DNA independently of catalytic activity. This DNA-binding function promotes DNA repair through recruitment of repair machinery at double-strand breaks and stalled replication forks. In light of these distinct but equally critical functions, it is meaningful to ask how SAMHD1 balances its dual roles as a multifunctional enzyme. This balance may be influenced by the numerous post-translational modifications (PTMs) that fine-tune SAMHD1 activity. Although these modifications have significant effects on cellular outcomes, the underlying mechanisms by which many of these PTMs alter SAMHD1 function is unknown. In this dissertation I address the effect of SAMHD1 regulation by phosphorylation, a critical open question that has perplexed the field for nearly a decade. I find that phosphorylation regulates SAMHD1 function by directing subcellular localization, with consequences for protein oxidation and cell cycle regulation. I also address the emerging function of SAMHD1 as a DNA-binding protein that promotes DNA repair. I find that DNA binds in the SAMHD1 regulatory site, revealing for the first time the structural basis of the SAMHD1-DNA complex. Taken together these findings contribute to the growing body of knowledge concerning the regulation of SAMHD1’s dual roles by PTMs with implications for cell cycle regulation, viral restriction, and DNA repair.
subject
DNA-binding
dNTPs
multifunctional enzyme
phosphorylation
SAMHD1
X-ray crystallography
contributor
Batalis, Stephanie (author)
Hollis, Tom (committee chair)
Poole, Leslie (committee member)
Perrino, Fred (committee member)
Lowther, Todd (committee member)
Pardee, Tim (committee member)
date
2022-01-15T09:35:32Z (accessioned)
2022 (issued)
degree
Biochemistry and Molecular Biology (discipline)
2023-01-14 (liftdate)
embargo
2023-01-14 (terms)
identifier
http://hdl.handle.net/10339/99393 (uri)
language
en (iso)
publisher
Wake Forest University
title
SAMHD1: ORTHOGONAL REGULATION OF A MULTIFUNCTIONAL ENZYME
type
Dissertation

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