Bloom syndrome DNA helicase deficiency is associated with oxidative stress and mitochondrial network changes
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Bloom syndrome DNA helicase deficiency is associated with oxidative stress and mitochondrial network changes. / Subramanian, Veena; Rodemoyer, Brian; Shastri, Vivek; Rasmussen, Lene J.; Desler, Claus; Schmidt, Kristina H.
In: Scientific Reports, Vol. 11, 2157, 2021.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Bloom syndrome DNA helicase deficiency is associated with oxidative stress and mitochondrial network changes
AU - Subramanian, Veena
AU - Rodemoyer, Brian
AU - Shastri, Vivek
AU - Rasmussen, Lene J.
AU - Desler, Claus
AU - Schmidt, Kristina H.
PY - 2021
Y1 - 2021
N2 - Bloom Syndrome (BS; OMIM #210900; ORPHA #125) is a rare genetic disorder that is associated with growth deficits, compromised immune system, insulin resistance, genome instability and extraordinary predisposition to cancer. Most efforts thus far have focused on understanding the role of the Bloom syndrome DNA helicase BLM as a recombination factor in maintaining genome stability and suppressing cancer. Here, we observed increased levels of reactive oxygen species (ROS) and DNA base damage in BLM-deficient cells, as well as oxidative-stress-dependent reduction in DNA replication speed. BLM-deficient cells exhibited increased mitochondrial mass, upregulation of mitochondrial transcription factor A (TFAM), higher ATP levels and increased respiratory reserve capacity. Cyclin B1, which acts in complex with cyclin-dependent kinase CDK1 to regulate mitotic entry and associated mitochondrial fission by phosphorylating mitochondrial fission protein Drp1, fails to be fully degraded in BLM-deficient cells and shows unscheduled expression in G1 phase cells. This failure to degrade cyclin B1 is accompanied by increased levels and persistent activation of Drp1 throughout mitosis and into G1 phase as well as mitochondrial fragmentation. This study identifies mitochondria-associated abnormalities in Bloom syndrome patient-derived and BLM-knockout cells and we discuss how these abnormalities may contribute to Bloom syndrome.
AB - Bloom Syndrome (BS; OMIM #210900; ORPHA #125) is a rare genetic disorder that is associated with growth deficits, compromised immune system, insulin resistance, genome instability and extraordinary predisposition to cancer. Most efforts thus far have focused on understanding the role of the Bloom syndrome DNA helicase BLM as a recombination factor in maintaining genome stability and suppressing cancer. Here, we observed increased levels of reactive oxygen species (ROS) and DNA base damage in BLM-deficient cells, as well as oxidative-stress-dependent reduction in DNA replication speed. BLM-deficient cells exhibited increased mitochondrial mass, upregulation of mitochondrial transcription factor A (TFAM), higher ATP levels and increased respiratory reserve capacity. Cyclin B1, which acts in complex with cyclin-dependent kinase CDK1 to regulate mitotic entry and associated mitochondrial fission by phosphorylating mitochondrial fission protein Drp1, fails to be fully degraded in BLM-deficient cells and shows unscheduled expression in G1 phase cells. This failure to degrade cyclin B1 is accompanied by increased levels and persistent activation of Drp1 throughout mitosis and into G1 phase as well as mitochondrial fragmentation. This study identifies mitochondria-associated abnormalities in Bloom syndrome patient-derived and BLM-knockout cells and we discuss how these abnormalities may contribute to Bloom syndrome.
U2 - 10.1038/s41598-021-81075-0
DO - 10.1038/s41598-021-81075-0
M3 - Journal article
C2 - 33495511
AN - SCOPUS:85099838904
VL - 11
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
M1 - 2157
ER -
ID: 256512574