AKT signaling promotes DNA damage accumulation and proliferation in polycystic kidney disease

Sarah E. Conduit, Elizabeth M. Davies, Lisa M. Ooms, Rajendra Gurung, Meagan J. Mcgrath, Sandra Hakim, Denny L. Cottle, Ian M. Smyth, Jennifer M. Dyson, Christina A. Mitchell

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Polycystic kidney disease (PKD) results in the formation of renal cysts that can impair function leading to renal failure. DNA damage accumulates in renal epithelial cells in PKD but the molecular mechanisms are unclear and are investigated here. Phosphoinositide 3- kinase (PI3K)/AKT signaling activates mammalian target of rapamycin complex 1 (mTORC1) and hyperactivation of mTORC1 is a common event in PKD, however, mTORC1 inhibitors have yielded disappointing results in clinical trials. Here we demonstrate AKT and mTORC1 hyperactivation in two representative murine PKD models (renal epithelial-specific Inpp5e knockout and collecting duct-specific Pkd1 deletion) and identify a downstream signaling network that contributes to DNA damage accumulation. Inpp5e- and Pkd1-null renal epithelial cells showed DNA damage including double-stranded DNA breaks associated with increased replication fork numbers, multinucleation and centrosome amplification. mTORC1 activated CAD, which promotes de novo pyrimidine synthesis, to sustain cell proliferation. AKT, but not mTORC1, inhibited the DNA repair/replication fork origin firing regulator TOPBP1, which impacts on DNA damage and cell proliferation. Notably, Inpp5e- and Pkd1-null renal epithelial cell spheroid formation defects were rescued by AKT inhibition. These data reveal that AKT hyperactivation contributes to DNA damage accumulation in multiple forms of PKD and cooperates with mTORC1 to promote cell proliferation. Hyperactivation of AKT may play a causal role in PKD by regulating DNA damage and cell proliferation, independent of mTORC1, and AKT inhibition may be a novel therapeutic approach for PKD.
Original languageEnglish
JournalHuman Molecular Genetics
DOIs
Publication statusAccepted/In press - 18 Oct 2019

Cite this

@article{88f90c5f207c4b619485d34bacd27831,
title = "AKT signaling promotes DNA damage accumulation and proliferation in polycystic kidney disease",
abstract = "Polycystic kidney disease (PKD) results in the formation of renal cysts that can impair function leading to renal failure. DNA damage accumulates in renal epithelial cells in PKD but the molecular mechanisms are unclear and are investigated here. Phosphoinositide 3- kinase (PI3K)/AKT signaling activates mammalian target of rapamycin complex 1 (mTORC1) and hyperactivation of mTORC1 is a common event in PKD, however, mTORC1 inhibitors have yielded disappointing results in clinical trials. Here we demonstrate AKT and mTORC1 hyperactivation in two representative murine PKD models (renal epithelial-specific Inpp5e knockout and collecting duct-specific Pkd1 deletion) and identify a downstream signaling network that contributes to DNA damage accumulation. Inpp5e- and Pkd1-null renal epithelial cells showed DNA damage including double-stranded DNA breaks associated with increased replication fork numbers, multinucleation and centrosome amplification. mTORC1 activated CAD, which promotes de novo pyrimidine synthesis, to sustain cell proliferation. AKT, but not mTORC1, inhibited the DNA repair/replication fork origin firing regulator TOPBP1, which impacts on DNA damage and cell proliferation. Notably, Inpp5e- and Pkd1-null renal epithelial cell spheroid formation defects were rescued by AKT inhibition. These data reveal that AKT hyperactivation contributes to DNA damage accumulation in multiple forms of PKD and cooperates with mTORC1 to promote cell proliferation. Hyperactivation of AKT may play a causal role in PKD by regulating DNA damage and cell proliferation, independent of mTORC1, and AKT inhibition may be a novel therapeutic approach for PKD.",
author = "Conduit, {Sarah E.} and Davies, {Elizabeth M.} and Ooms, {Lisa M.} and Rajendra Gurung and Mcgrath, {Meagan J.} and Sandra Hakim and Cottle, {Denny L.} and Smyth, {Ian M.} and Dyson, {Jennifer M.} and Mitchell, {Christina A.}",
year = "2019",
month = "10",
day = "18",
doi = "10.1093/hmg/ddz232",
language = "English",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",

}

AKT signaling promotes DNA damage accumulation and proliferation in polycystic kidney disease. / Conduit, Sarah E.; Davies, Elizabeth M.; Ooms, Lisa M.; Gurung, Rajendra; Mcgrath, Meagan J.; Hakim, Sandra; Cottle, Denny L.; Smyth, Ian M.; Dyson, Jennifer M.; Mitchell, Christina A.

In: Human Molecular Genetics, 18.10.2019.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - AKT signaling promotes DNA damage accumulation and proliferation in polycystic kidney disease

AU - Conduit, Sarah E.

AU - Davies, Elizabeth M.

AU - Ooms, Lisa M.

AU - Gurung, Rajendra

AU - Mcgrath, Meagan J.

AU - Hakim, Sandra

AU - Cottle, Denny L.

AU - Smyth, Ian M.

AU - Dyson, Jennifer M.

AU - Mitchell, Christina A.

PY - 2019/10/18

Y1 - 2019/10/18

N2 - Polycystic kidney disease (PKD) results in the formation of renal cysts that can impair function leading to renal failure. DNA damage accumulates in renal epithelial cells in PKD but the molecular mechanisms are unclear and are investigated here. Phosphoinositide 3- kinase (PI3K)/AKT signaling activates mammalian target of rapamycin complex 1 (mTORC1) and hyperactivation of mTORC1 is a common event in PKD, however, mTORC1 inhibitors have yielded disappointing results in clinical trials. Here we demonstrate AKT and mTORC1 hyperactivation in two representative murine PKD models (renal epithelial-specific Inpp5e knockout and collecting duct-specific Pkd1 deletion) and identify a downstream signaling network that contributes to DNA damage accumulation. Inpp5e- and Pkd1-null renal epithelial cells showed DNA damage including double-stranded DNA breaks associated with increased replication fork numbers, multinucleation and centrosome amplification. mTORC1 activated CAD, which promotes de novo pyrimidine synthesis, to sustain cell proliferation. AKT, but not mTORC1, inhibited the DNA repair/replication fork origin firing regulator TOPBP1, which impacts on DNA damage and cell proliferation. Notably, Inpp5e- and Pkd1-null renal epithelial cell spheroid formation defects were rescued by AKT inhibition. These data reveal that AKT hyperactivation contributes to DNA damage accumulation in multiple forms of PKD and cooperates with mTORC1 to promote cell proliferation. Hyperactivation of AKT may play a causal role in PKD by regulating DNA damage and cell proliferation, independent of mTORC1, and AKT inhibition may be a novel therapeutic approach for PKD.

AB - Polycystic kidney disease (PKD) results in the formation of renal cysts that can impair function leading to renal failure. DNA damage accumulates in renal epithelial cells in PKD but the molecular mechanisms are unclear and are investigated here. Phosphoinositide 3- kinase (PI3K)/AKT signaling activates mammalian target of rapamycin complex 1 (mTORC1) and hyperactivation of mTORC1 is a common event in PKD, however, mTORC1 inhibitors have yielded disappointing results in clinical trials. Here we demonstrate AKT and mTORC1 hyperactivation in two representative murine PKD models (renal epithelial-specific Inpp5e knockout and collecting duct-specific Pkd1 deletion) and identify a downstream signaling network that contributes to DNA damage accumulation. Inpp5e- and Pkd1-null renal epithelial cells showed DNA damage including double-stranded DNA breaks associated with increased replication fork numbers, multinucleation and centrosome amplification. mTORC1 activated CAD, which promotes de novo pyrimidine synthesis, to sustain cell proliferation. AKT, but not mTORC1, inhibited the DNA repair/replication fork origin firing regulator TOPBP1, which impacts on DNA damage and cell proliferation. Notably, Inpp5e- and Pkd1-null renal epithelial cell spheroid formation defects were rescued by AKT inhibition. These data reveal that AKT hyperactivation contributes to DNA damage accumulation in multiple forms of PKD and cooperates with mTORC1 to promote cell proliferation. Hyperactivation of AKT may play a causal role in PKD by regulating DNA damage and cell proliferation, independent of mTORC1, and AKT inhibition may be a novel therapeutic approach for PKD.

U2 - 10.1093/hmg/ddz232

DO - 10.1093/hmg/ddz232

M3 - Article

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

ER -