Scheibye-Knudsen Morten, Tseng Anne, Borch Jensen Martin, Scheibye-Alsing Karsten, Fang Evandro Fei, Iyama Teruaki, Bharti Sanjay Kumar, Marosi Krisztina, Froetscher Lynn, Kassahun Henok, Eckley David Mark, Maul Robert W, Bastian Paul, De Supriyo, Ghosh Soumita, Nilsen Hilde, Goldberg Ilya G, Mattson Mark P, Wilson David M, Brosh Robert M, Gorospe Myriam, Bohr Vilhelm A
Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, 2300 Copenhagen, Denmark;
Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224.
Proc Natl Acad Sci U S A. 2016 Nov 1;113(44):12502-12507. doi: 10.1073/pnas.1610198113. Epub 2016 Oct 18.
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.
科凯恩综合征是一种由CSA或CSB基因突变引起的神经退行性加速衰老疾病。尽管科凯恩综合征的发病机制仍不清楚，但最近的研究表明线粒体功能障碍与疾病进展有关。在此，我们提供证据表明，神经母细胞瘤细胞系中CSA或CSB的缺失会导致核糖体DNA转录缺陷和DNA损伤传感器聚ADP核糖聚合酶1（PARP1）激活所引起的线粒体功能障碍。事实上，抑制核糖体DNA转录会导致多种细胞系出现线粒体功能障碍。此外，机器学习算法预测，核糖体DNA（rDNA）转录存在缺陷的疾病有线粒体功能障碍，相应地，当敲低参与rDNA转录的因子时也会发现这种情况。从机制上讲，CSA或CSB的缺失会导致神经母细胞瘤细胞系中的聚合酶在非B型DNA处停滞，特别是在G-四链体结构处，并且重组CSB可以解开G-四链体结构。事实上，G-四链体结构的稳定会激活PARP1并导致秀丽隐杆线虫加速衰老。总之，这项研究支持核糖体DNA转录受损在科凯恩综合征中的作用，并表明转录偶联的二级结构解析可能是一种抑制DNA损伤反应虚假激活的机制。
