title: Alpha-synuclein functions in the nucleus to protect against hydroxyurea-induced replication stress in yeast.
abstract: Hydroxyurea (HU) inhibits ribonucleotide reductase (RNR), which catalyzes the rate-limiting synthesis of deoxyribonucleotides for DNA replication. HU is used to treat HIV, sickle-cell anemia and some cancers. We found that, compared with vector control cells, low levels of alpha-synuclein (α-syn) protect S. cerevisiae cells from the growth inhibition and reactive oxygen species (ROS) accumulation induced by HU. Analysis of this effect using different α-syn mutants revealed that the α-syn protein functions in the nucleus and not the cytoplasm to modulate S-phase checkpoint responses: α-syn up-regulates histone acetylation and RNR levels, maintains helicase minichromosome maintenance protein complexes (Mcm2-7) on chromatin and inhibits HU-induced ROS accumulation. Strikingly, when residues 2-10 or 96-140 are deleted, this protective function of α-syn in the nucleus is abolished. Understanding the mechanism by which α-syn protects against HU could expand our knowledge of the normal function of this neuronal protein.
authors.affiliation: Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130-3932, USA.
authors.forename: Xianpeng
authors.initials: X
authors.lastname: Liu
authors.forename: Yong Joo
authors.initials: YJ
authors.lastname: Lee
authors.forename: Liang-Chun
authors.initials: LC
authors.lastname: Liou
authors.forename: Qun
authors.initials: Q
authors.lastname: Ren
authors.forename: Zhaojie
authors.initials: Z
authors.lastname: Zhang
authors.forename: Shaoxiao
authors.initials: S
authors.lastname: Wang
authors.forename: Stephan N
authors.initials: SN
authors.lastname: Witt
mesh_terms: D002467:Cell Nucleus / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D006918:Hydroxyurea / Q000494:pharmacology*; D012264:Ribonucleotide Reductases / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: D051844:alpha-Synuclein; D012264:Ribonucleotide Reductases; D006918:Hydroxyurea