TY - JOUR
T1 - Rev1 contributes to proper mitochondrial function via the PARP-NAD(+)-SIRT1-PGC1 alpha axis
AU - Fakouri, Nima Borhan
AU - Durhuus, Jon Ambaek
AU - Regnell, Christine Elisabeth
AU - Angleys, Maria
AU - Desler, Claus
AU - Hasan-Olive, Mahdi
AU - Martin-Pardillos, Ana
AU - Tsaalbi-Shtylik, Anastasia
AU - Thomsen, Kirsten
AU - Lauritzen, Martin
AU - Bohr, Vilhelm A.
AU - de Wind, Niels
AU - Bergersen, Linda Hildegard
AU - Rasmussen, Lene Juel
N1 - Author Correction: Rev1 contributes to proper mitochondrial function via the PARP-NAD+-SIRT1-PGC1α axis DOI: 10.1038/s41598-018-20586-9
PY - 2017
Y1 - 2017
N2 - Nucleic acids, which constitute the genetic material of all organisms, are continuously exposed to endogenous and exogenous damaging agents, representing a significant challenge to genome stability and genome integrity over the life of a cell or organism. Unrepaired DNA lesions, such as single- and double-stranded DNA breaks (SSBs and DSBs), and single-stranded gaps can block progression of the DNA replication fork, causing replicative stress and/or cell cycle arrest. However, translesion synthesis (TLS) DNA polymerases, such as Rev1, have the ability to bypass some DNA lesions, which can circumvent the process leading to replication fork arrest and minimize replicative stress. Here, we show that Rev1-deficiency in mouse embryo fibroblasts or mouse liver tissue is associated with replicative stress and mitochondrial dysfunction. In addition, Rev1-deficiency is associated with high poly(ADP) ribose polymerase 1 (PARP1) activity, low endogenous NAD+, low expression of SIRT1 and PGC1α and low adenosine monophosphate (AMP)-activated kinase (AMPK) activity. We conclude that replication stress via Rev1-deficiency contributes to metabolic stress caused by compromized mitochondrial function via the PARP-NAD+-SIRT1-PGC1α axis.
AB - Nucleic acids, which constitute the genetic material of all organisms, are continuously exposed to endogenous and exogenous damaging agents, representing a significant challenge to genome stability and genome integrity over the life of a cell or organism. Unrepaired DNA lesions, such as single- and double-stranded DNA breaks (SSBs and DSBs), and single-stranded gaps can block progression of the DNA replication fork, causing replicative stress and/or cell cycle arrest. However, translesion synthesis (TLS) DNA polymerases, such as Rev1, have the ability to bypass some DNA lesions, which can circumvent the process leading to replication fork arrest and minimize replicative stress. Here, we show that Rev1-deficiency in mouse embryo fibroblasts or mouse liver tissue is associated with replicative stress and mitochondrial dysfunction. In addition, Rev1-deficiency is associated with high poly(ADP) ribose polymerase 1 (PARP1) activity, low endogenous NAD+, low expression of SIRT1 and PGC1α and low adenosine monophosphate (AMP)-activated kinase (AMPK) activity. We conclude that replication stress via Rev1-deficiency contributes to metabolic stress caused by compromized mitochondrial function via the PARP-NAD+-SIRT1-PGC1α axis.
UR - https://doi.org/10.1038/s41598-018-20586-9
U2 - 10.1038/s41598-017-12662-3
DO - 10.1038/s41598-017-12662-3
M3 - Journal article
C2 - 28970491
VL - 7
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
M1 - 12480
ER -