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Mck1 defines a key S-phase checkpoint effector in response to various degrees of replication threats

Journal article
Authors X. L. Li
Xuejiao Jin
S. Sharma
X. J. Liu
J. X. Zhang
Y. L. Niu
J. N. Li
Z. Li
J. J. Zhang
Q. H. Cao
W. Y. Hou
L. L. Du
Liu Beidong
H. Q. Lou
Published in Plos Genetics
Volume 15
Issue 8
ISSN 1553-7404
Publication year 2019
Published at Department of Chemistry and Molecular Biology
Language en
Links dx.doi.org/10.1371/journal.pgen.100...
Keywords ribonucleotide reductase inhibitor, DNA-damage response, nuclear import, protein-kinase, stress, transcription, localization, survival, mechanisms, expansion, Genetics & Heredity
Subject categories Genetics

Abstract

The S-phase checkpoint plays an essential role in regulation of the ribonucleotide reductase (RNR) activity to maintain the dNTP pools. How eukaryotic cells respond appropriately to different levels of replication threats remains elusive. Here, we have identified that a conserved GSK-3 kinase Mck1 cooperates with Dun1 in regulating this process. Deleting MCK1 sensitizes dun1 Delta to hydroxyurea (HU) reminiscent of mec1 Delta or rad53 Delta. While Mck1 is downstream of Rad53, it does not participate in the post-translational regulation of RNR as Dun1 does. Mck1 phosphorylates and releases the Crt1 repressor from the promoters of DNA damage-inducible genes as RNR2-4 and HUG1. Hug1, an Rnr2 inhibitor normally silenced, is induced as a counterweight to excessive RNR. When cells suffer a more severe threat, Mck1 inhibits HUG1 transcription. Consistently, only a combined deletion of HUG1 and CRT1, confers a dramatic boost of dNTP levels and the survival of mck1 Delta dun1 Delta or mec1 Delta cells assaulted by a lethal dose of HU. These findings reveal the division-of-labor between Mck1 and Dun1 at the S-phase checkpoint pathway to fine-tune dNTP homeostasis. Author summary The appropriate amount and balance of four dNTPs are crucial for all cells correctly copying and passing on their genetic material generation by generation. Eukaryotes have developed an alert and response system to deal with the disturbance. Here, we uncovered a second-level effector branch. It is activated by the upstream surveillance kinase cascade, which can induce the expression of dNTP-producing enzymes. It can also reduce the inhibitor of these enzymes to further boost their activity according to the degrees of threats. These findings suggest a multi-level response system to guarantee the appropriate dNTP supply, which is essential to maintain genetic stability under various environmental challenges.

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