TY - JOUR
T1 - Cockayne syndrome group A and B proteins converge on transcription-linked resolution of non-B DNA
AU - Scheibye-Knudsen, Morten
AU - Tseng, Anne
AU - Jensen, Martin Borch
AU - Scheibye-Alsing, Karsten
AU - Fang, Evandro Fei
AU - Iyama, Teruaki
AU - Bharti, Sanjay Kumar
AU - Marosi, Krisztina
AU - Froetscher, Lynn
AU - Kassahun, Henok
AU - Eckley, David Mark
AU - Maul, Robert W.
AU - Bastian, Paul
AU - De, Supriyo
AU - Ghosh, Soumita
AU - Nilsen, Hilde
AU - Goldberg, Ilya G.
AU - Mattson, Mark P.
AU - Wilson, David M.
AU - Brosh, Robert M.
AU - Gorospe, Myriam
AU - Bohr, Vilhelm A.
PY - 2016/11/1
Y1 - 2016/11/1
N2 - Cockayne syndrome is a neurodegenerative accelerated aging disorder caused by mutations in the CSA or CSB genes. Although the pathogenesis of Cockayne syndrome has remained elusive, recent work implicates mitochondrial dysfunction in the disease progression. Here,we present evidence that loss of CSA or CSB in a neuroblastoma cell line converges on mitochondrial dysfunction caused by defects in ribosomal DNA transcription and activation of the DNA damage sensor poly-ADP ribose polymerase 1 (PARP1). Indeed, inhibition of ribosomal DNA transcription leads to mitochondrial dysfunction in a number of cell lines. Furthermore, machine-learning algorithms predict that diseases with defects in ribosomal DNA (rDNA) transcription have mitochondrial dysfunction, and, accordingly, this is found when factors involved in rDNA transcription are knocked down. Mechanistically, loss of CSA or CSB leads to polymerase stalling at non-B DNA in a neuroblastoma cell line, in particular at G-quadruplex structures, and recombinant CSB can melt G-quadruplex structures. Indeed, stabilization of G-quadruplex structures activates PARP1 and leads to accelerated aging in Caenorhabditis elegans. In conclusion, this work supports a role for impaired ribosomal DNA transcription in Cockayne syndrome and suggests that transcription-coupled resolution of secondary structures may be a mechanism to repress spurious activation of a DNA damage response.
AB - Cockayne syndrome is a neurodegenerative accelerated aging disorder caused by mutations in the CSA or CSB genes. Although the pathogenesis of Cockayne syndrome has remained elusive, recent work implicates mitochondrial dysfunction in the disease progression. Here,we present evidence that loss of CSA or CSB in a neuroblastoma cell line converges on mitochondrial dysfunction caused by defects in ribosomal DNA transcription and activation of the DNA damage sensor poly-ADP ribose polymerase 1 (PARP1). Indeed, inhibition of ribosomal DNA transcription leads to mitochondrial dysfunction in a number of cell lines. Furthermore, machine-learning algorithms predict that diseases with defects in ribosomal DNA (rDNA) transcription have mitochondrial dysfunction, and, accordingly, this is found when factors involved in rDNA transcription are knocked down. Mechanistically, loss of CSA or CSB leads to polymerase stalling at non-B DNA in a neuroblastoma cell line, in particular at G-quadruplex structures, and recombinant CSB can melt G-quadruplex structures. Indeed, stabilization of G-quadruplex structures activates PARP1 and leads to accelerated aging in Caenorhabditis elegans. In conclusion, this work supports a role for impaired ribosomal DNA transcription in Cockayne syndrome and suggests that transcription-coupled resolution of secondary structures may be a mechanism to repress spurious activation of a DNA damage response.
KW - Aging
KW - Cockayne syndrome
KW - CSA
KW - CSB
KW - Nucleolus
KW - Polymerase I transcription
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U2 - 10.1073/pnas.1610198113
DO - 10.1073/pnas.1610198113
M3 - Article
C2 - 27791127
AN - SCOPUS:84993967427
VL - 113
SP - 12502
EP - 12507
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 44
ER -