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., III

AU - Brosh, Robert M., Jr.

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 - Cockayne syndrome

KW - aging

KW - polymerase

KW - transcription

KW - nucleolus

KW - CSA

KW - CSB

U2 - 10.1073/pnas.1610198113

DO - 10.1073/pnas.1610198113

M3 - Journal article

C2 - 27791127

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 -