PMID- 31413202
OWN - NLM
STAT- MEDLINE
DCOM- 20200324
LR  - 20211204
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 116
IP  - 35
DP  - 2019 Aug 27
TI  - A pathway linking translation stress to checkpoint kinase 2 signaling in 
      Neurospora crassa.
PG  - 17271-17279
LID - 10.1073/pnas.1815396116 [doi]
AB  - Checkpoint kinase 2 (CHK-2) is a key component of the DNA damage response (DDR). 
      CHK-2 is activated by the PIP3-kinase-like kinases (PI3KKs) ataxia telangiectasia 
      mutated (ATM) and ataxia telangiectasia and Rad3-related protein (ATR), and in 
      metazoan also by DNA-dependent protein kinase catalytic subunit (DNA-PKcs). These 
      DNA damage-dependent activation pathways are conserved and additional activation 
      pathways of CHK-2 are not known. Here we show that PERIOD-4 (PRD-4), the CHK-2 
      ortholog of Neurospora crassa, is part of a signaling pathway that is activated 
      when protein translation is compromised. Translation stress induces 
      phosphorylation of PRD-4 by a PI3KK distinct from ATM and ATR. Our data indicate 
      that the activating PI3KK is mechanistic target of rapamycin (mTOR). We provide 
      evidence that translation stress is sensed by unbalancing the expression levels 
      of an unstable protein phosphatase that antagonizes phosphorylation of PRD-4 by 
      mTOR complex 1 (TORC1). Hence, Neurospora mTOR and PRD-4 appear to coordinate 
      metabolic state and cell cycle progression.
CI  - Copyright (c) 2019 the Author(s). Published by PNAS.
FAU - Diernfellner, Axel C R
AU  - Diernfellner ACR
AD  - Biochemistry Center, Heidelberg University, D-69120 Heidelberg, Germany 
      axel.diernfellner@bzh.uni-heidelberg.de michael.brunner@bzh.uni-heidelberg.de.
FAU - Lauinger, Linda
AU  - Lauinger L
AD  - Biochemistry Center, Heidelberg University, D-69120 Heidelberg, Germany.
FAU - Shostak, Anton
AU  - Shostak A
AD  - Biochemistry Center, Heidelberg University, D-69120 Heidelberg, Germany.
FAU - Brunner, Michael
AU  - Brunner M
AD  - Biochemistry Center, Heidelberg University, D-69120 Heidelberg, Germany 
      axel.diernfellner@bzh.uni-heidelberg.de michael.brunner@bzh.uni-heidelberg.de.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190814
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Fungal Proteins)
RN  - EC 2.7.1.11 (Checkpoint Kinase 2)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Checkpoint Kinase 2/genetics/*metabolism
MH  - Fungal Proteins/genetics/*metabolism
MH  - Neurospora crassa/*enzymology/genetics
MH  - *Protein Biosynthesis
MH  - *Signal Transduction
MH  - *Stress, Physiological
MH  - TOR Serine-Threonine Kinases/genetics/metabolism
PMC - PMC6717302
OTO - NOTNLM
OT  - Neurospora crassa
OT  - checkpoint kinase 2
OT  - circadian clock
OT  - mTOR
OT  - translation inhibition
COIS- The authors declare no conflict of interest.
EDAT- 2019/08/16 06:00
MHDA- 2020/03/25 06:00
PMCR- 2019/08/14
CRDT- 2019/08/16 06:00
PHST- 2019/08/16 06:00 [pubmed]
PHST- 2020/03/25 06:00 [medline]
PHST- 2019/08/16 06:00 [entrez]
PHST- 2019/08/14 00:00 [pmc-release]
AID - 1815396116 [pii]
AID - 201815396 [pii]
AID - 10.1073/pnas.1815396116 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2019 Aug 27;116(35):17271-17279. doi: 
      10.1073/pnas.1815396116. Epub 2019 Aug 14.