title: 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: Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, 2300 Copenhagen, Denmark; mscheibye@sund.ku.dk vbohr@nih.gov.|Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224.
authors: Morten
authors: M
authors: Scheibye-Knudsen
authors: Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224.
authors: Anne
authors: A
authors: Tseng
authors: Buck Institute for Research on Aging, Novato, CA 94945.
authors: Martin
authors: M
authors: Borch Jensen
authors: Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, 2300 Copenhagen, Denmark.
authors: Karsten
authors: K
authors: Scheibye-Alsing
authors: Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224.
authors: Evandro Fei
authors: EF
authors: Fang
authors: Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224.
authors: Teruaki
authors: T
authors: Iyama
authors: Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224.
authors: Sanjay Kumar
authors: SK
authors: Bharti
authors: Laboratory of Neuroscience, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224.
authors: Krisztina
authors: K
authors: Marosi
authors: Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224.
authors: Lynn
authors: L
authors: Froetscher
authors: Institute of Clinical Medicine, 0167 Lorenskog, Norway.
authors: Henok
authors: H
authors: Kassahun
authors: Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224.
authors: David Mark
authors: DM
authors: Eckley
authors: Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224.
authors: Robert W
authors: RW
authors: Maul
authors: Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224.
authors: Paul
authors: P
authors: Bastian
authors: Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224.
authors: Supriyo
authors: S
authors: De
authors: Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224.
authors: Soumita
authors: S
authors: Ghosh
authors: Institute of Clinical Medicine, 0167 Lorenskog, Norway.|University of Oslo and Akershus University Hospital, 0167 Lorenskog, Norway.
authors: Hilde
authors: H
authors: Nilsen
authors: Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224.
authors: Ilya G
authors: IG
authors: Goldberg
authors: Laboratory of Neuroscience, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224.
authors: Mark P
authors: MP
authors: Mattson
authors: Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224.
authors: David M
authors: DM
authors: Wilson
authors: Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224.
authors: Robert M
authors: RM
authors: Brosh
authors: Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224.
authors: Myriam
authors: M
authors: Gorospe
authors: Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224; mscheibye@sund.ku.dk vbohr@nih.gov.
authors: Vilhelm A
authors: VA
authors: Bohr
mesh_terms: D045744:Cell Line, Tumor; D003057:Cockayne Syndrome / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D004265:DNA Helicases / Q000235:genetics* / Q000378:metabolism; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000235:genetics* / Q000378:metabolism; D004273:DNA, Neoplasm / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D004275:DNA, Ribosomal / Q000235:genetics; D054856:G-Quadruplexes; D055785:Gene Knockdown Techniques; D006801:Humans; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000235:genetics / Q000378:metabolism; D000075223:Poly-ADP-Ribose Binding Proteins / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D004273:DNA, Neoplasm; D004275:DNA, Ribosomal; C095472:ERCC8 protein, human; D000075223:Poly-ADP-Ribose Binding Proteins; D014157:Transcription Factors; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D004265:DNA Helicases; C078673:ERCC6 protein, human; D045643:DNA Repair Enzymes
keywords: CSA; CSB; Cockayne syndrome; aging; nucleolus; polymerase I transcription