Proteins in the Nutrient-Sensing and DNA damage checkpoint pathways cooperate to restrain mitotic progression following DNA damage

Jennifer S. Searle, Matthew Wood, Mandeep Kaur, David V. Tobin, Yolanda Sanchez

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Checkpoint pathways regulate genomic integrity in part by blocking anaphase until all chromosomes have been completely replicated, repaired, and correctly aligned on the spindle. In Saccharomyces cerevisiae, DNA damage and mono-oriented or unattached kinetochores trigger checkpoint pathways that bifurcate to regulate both the metaphase to anaphase transition and mitotic exit. The sensor-associated kinase, Mec1, phosphorylates two downstream kinases, Chk1 and Rad53. Activation of Chk1 and Rad53 prevents anaphase and causes inhibition of the mitotic exit network. We have previously shown that the PKA pathway plays a role in blocking securin and Clb2 destruction following DNA damage. Here we show that the Mec1 DNA damage checkpoint regulates phosphorylation of the regulatory (R) subunit of PKA following DNA damage and that the phosphorylated R subunit has a role in restraining mitosis following DNA damage. In addition we found that proteins known to regulate PKA in response to nutrients and stress either by phosphorylation of the R subunit or regulating levels of cAMP are required for the role of PKA in the DNA damage checkpoint. Our data indicate that there is cross-talk between the DNA damage checkpoint and the proteins that integrate nutrient and stress signals to regulate PKA.

Original languageEnglish (US)
Article numbere1002176
JournalPLoS genetics
Volume7
Issue number7
DOIs
StatePublished - Jul 1 2011
Externally publishedYes

Fingerprint

DNA damage
DNA Damage
DNA
Food
damage
protein
nutrient
nutrients
Anaphase
anaphase
Proteins
proteins
phosphorylation
phosphotransferases (kinases)
Securin
Phosphorylation
Kinetochores
kinetochores
Metaphase
metaphase

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Cite this

Proteins in the Nutrient-Sensing and DNA damage checkpoint pathways cooperate to restrain mitotic progression following DNA damage. / Searle, Jennifer S.; Wood, Matthew; Kaur, Mandeep; Tobin, David V.; Sanchez, Yolanda.

In: PLoS genetics, Vol. 7, No. 7, e1002176, 01.07.2011.

Research output: Contribution to journalArticle

@article{823ece020b0f4b9eb45e3cf272c72749,
title = "Proteins in the Nutrient-Sensing and DNA damage checkpoint pathways cooperate to restrain mitotic progression following DNA damage",
abstract = "Checkpoint pathways regulate genomic integrity in part by blocking anaphase until all chromosomes have been completely replicated, repaired, and correctly aligned on the spindle. In Saccharomyces cerevisiae, DNA damage and mono-oriented or unattached kinetochores trigger checkpoint pathways that bifurcate to regulate both the metaphase to anaphase transition and mitotic exit. The sensor-associated kinase, Mec1, phosphorylates two downstream kinases, Chk1 and Rad53. Activation of Chk1 and Rad53 prevents anaphase and causes inhibition of the mitotic exit network. We have previously shown that the PKA pathway plays a role in blocking securin and Clb2 destruction following DNA damage. Here we show that the Mec1 DNA damage checkpoint regulates phosphorylation of the regulatory (R) subunit of PKA following DNA damage and that the phosphorylated R subunit has a role in restraining mitosis following DNA damage. In addition we found that proteins known to regulate PKA in response to nutrients and stress either by phosphorylation of the R subunit or regulating levels of cAMP are required for the role of PKA in the DNA damage checkpoint. Our data indicate that there is cross-talk between the DNA damage checkpoint and the proteins that integrate nutrient and stress signals to regulate PKA.",
author = "Searle, {Jennifer S.} and Matthew Wood and Mandeep Kaur and Tobin, {David V.} and Yolanda Sanchez",
year = "2011",
month = "7",
day = "1",
doi = "10.1371/journal.pgen.1002176",
language = "English (US)",
volume = "7",
journal = "PLoS Genetics",
issn = "1553-7390",
publisher = "Public Library of Science",
number = "7",

}

TY - JOUR

T1 - Proteins in the Nutrient-Sensing and DNA damage checkpoint pathways cooperate to restrain mitotic progression following DNA damage

AU - Searle, Jennifer S.

AU - Wood, Matthew

AU - Kaur, Mandeep

AU - Tobin, David V.

AU - Sanchez, Yolanda

PY - 2011/7/1

Y1 - 2011/7/1

N2 - Checkpoint pathways regulate genomic integrity in part by blocking anaphase until all chromosomes have been completely replicated, repaired, and correctly aligned on the spindle. In Saccharomyces cerevisiae, DNA damage and mono-oriented or unattached kinetochores trigger checkpoint pathways that bifurcate to regulate both the metaphase to anaphase transition and mitotic exit. The sensor-associated kinase, Mec1, phosphorylates two downstream kinases, Chk1 and Rad53. Activation of Chk1 and Rad53 prevents anaphase and causes inhibition of the mitotic exit network. We have previously shown that the PKA pathway plays a role in blocking securin and Clb2 destruction following DNA damage. Here we show that the Mec1 DNA damage checkpoint regulates phosphorylation of the regulatory (R) subunit of PKA following DNA damage and that the phosphorylated R subunit has a role in restraining mitosis following DNA damage. In addition we found that proteins known to regulate PKA in response to nutrients and stress either by phosphorylation of the R subunit or regulating levels of cAMP are required for the role of PKA in the DNA damage checkpoint. Our data indicate that there is cross-talk between the DNA damage checkpoint and the proteins that integrate nutrient and stress signals to regulate PKA.

AB - Checkpoint pathways regulate genomic integrity in part by blocking anaphase until all chromosomes have been completely replicated, repaired, and correctly aligned on the spindle. In Saccharomyces cerevisiae, DNA damage and mono-oriented or unattached kinetochores trigger checkpoint pathways that bifurcate to regulate both the metaphase to anaphase transition and mitotic exit. The sensor-associated kinase, Mec1, phosphorylates two downstream kinases, Chk1 and Rad53. Activation of Chk1 and Rad53 prevents anaphase and causes inhibition of the mitotic exit network. We have previously shown that the PKA pathway plays a role in blocking securin and Clb2 destruction following DNA damage. Here we show that the Mec1 DNA damage checkpoint regulates phosphorylation of the regulatory (R) subunit of PKA following DNA damage and that the phosphorylated R subunit has a role in restraining mitosis following DNA damage. In addition we found that proteins known to regulate PKA in response to nutrients and stress either by phosphorylation of the R subunit or regulating levels of cAMP are required for the role of PKA in the DNA damage checkpoint. Our data indicate that there is cross-talk between the DNA damage checkpoint and the proteins that integrate nutrient and stress signals to regulate PKA.

UR - http://www.scopus.com/inward/record.url?scp=79960968062&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79960968062&partnerID=8YFLogxK

U2 - 10.1371/journal.pgen.1002176

DO - 10.1371/journal.pgen.1002176

M3 - Article

VL - 7

JO - PLoS Genetics

JF - PLoS Genetics

SN - 1553-7390

IS - 7

M1 - e1002176

ER -