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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 (?-syn) protect S. cerevisiae cells from the growth inhibition and reactive oxygen species (ROS) accumulation induced by HU. Analysis of this effect using different ?-syn mutants revealed that the ?-syn protein functions in the nucleus and not the cytoplasm to modulate S-phase checkpoint responses: ?-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 ?-syn in the nucleus is abolished. Understanding the mechanism by which ?-syn protects against HU could expand our knowledge of the normal function of this neuronal protein.

SUBMITTER: Liu X 

PROVIDER: S-EPMC3153305 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Alpha-synuclein functions in the nucleus to protect against hydroxyurea-induced replication stress in yeast.

Liu Xianpeng X   Lee Yong Joo YJ   Liou Liang-Chun LC   Ren Qun Q   Zhang Zhaojie Z   Wang Shaoxiao S   Witt Stephan N SN  

Human molecular genetics 20110603 17

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  ...[more]

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