Format

Send to

Choose Destination
Proc Natl Acad Sci U S A. 2016 Nov 1;113(44):12502-12507. Epub 2016 Oct 18.

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

Author information

1
Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, 2300 Copenhagen, Denmark; mscheibye@sund.ku.dk vbohr@nih.gov.
2
Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224.
3
Buck Institute for Research on Aging, Novato, CA 94945.
4
Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, 2300 Copenhagen, Denmark.
5
Laboratory of Neuroscience, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224.
6
Institute of Clinical Medicine, 0167 Lorenskog, Norway.
7
Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224.
8
Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224.
9
Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224.
10
University of Oslo and Akershus University Hospital, 0167 Lorenskog, Norway.
11
Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224; mscheibye@sund.ku.dk vbohr@nih.gov.

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.

KEYWORDS:

CSA; CSB; Cockayne syndrome; aging; nucleolus; polymerase I transcription

PMID:
27791127
PMCID:
PMC5098674
DOI:
10.1073/pnas.1610198113
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center