Cockayne syndrome group A and B proteins converge on transcription-linked resolution of non-B DNA.

Abstract

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.

• Authors: Morten Scheibye-Knudsen, Anne Tseng, Martin Borch Jensen, Karsten Scheibye-Alsing, Evandro Fei Fang, Teruaki Iyama, Sanjay Kumar Bharti, Krisztina Marosi, Lynn Froetscher, Henok Kassahun, David Mark Eckley, Robert W Maul, Paul Bastian, Supriyo De, Soumita Ghosh, Hilde Nilsen, Ilya G Goldberg, Mark P Mattson, David M Wilson 3rd, Robert M Brosh Jr, Myriam Gorospe, Vilhelm A Bohr
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 113 Issue 44 Pg. 12502-12507 (11 01 2016) ISSN: 1091-6490 [Electronic] United States
• PMID: 27791127 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• DNA, Neoplasm
• DNA, Ribosomal
• ERCC8 protein, human
• Poly-ADP-Ribose Binding Proteins
• Transcription Factors
• PARP1 protein, human
• Poly (ADP-Ribose) Polymerase-1
• DNA Helicases
• ERCC6 protein, human
• DNA Repair Enzymes

Topics

• Cell Line, Tumor
• Cockayne Syndrome (genetics, metabolism)
• DNA Damage
• DNA Helicases (genetics, metabolism)
• DNA Repair
• DNA Repair Enzymes (genetics, metabolism)
• DNA, Neoplasm (chemistry, genetics, metabolism)
• DNA, Ribosomal (genetics)
• G-Quadruplexes
• Gene Knockdown Techniques
• Humans
• Neuroblastoma (genetics, metabolism, pathology)
• Poly (ADP-Ribose) Polymerase-1 (genetics, metabolism)
• Poly-ADP-Ribose Binding Proteins (genetics, metabolism)
• Transcription Factors (genetics, metabolism)
• Transcription, Genetic