Cockayne syndrome (CS) is a devastating autosomal recessive disease characterized by neurodegeneration, cachexia, and accelerated aging. 80% of the cases are caused by mutations in the CS complementation group B (CSB) gene known to be involved in DNA repair and transcription. In CS cells, there are deficiencies in the repair of oxidative DNA damage in the nuclear and mitochondrial DNA, and this may be a major underlying cause of the disease. Previously we found that CSB-deficient cells accumulate oxidized bases, 8-hydroxyguanine and 8-hydroxyadenine, after oxidative stress, consistent with the observation that CSB and oxoguanine DNA glycosylase (OGG1), the major DNA glycosylase for 8-oxoG repair, are in a complex in vivo. Previously we demonstrated that the CSB protein also interacts with PARP1, a protein involved in the early steps of single-strand break repair, and that these two proteins cooperate in the cellular responses to oxidative stress. CSB is a substrate for PARP-1 ribosylation and it is likely that these two proteins function together in the process of base excision. Our results indicate that the CSB protein plays an important role in the repair of oxidative DNA damage and that accumulation of unrepaired lesions, particular in target tissues, like the brain, may be relevant to the CS pathology, which is characterized by severe early onset neurodegeneration. To further explore the role of CSB in mitochondria, we are pursuing the proposal that CSB functions in mitochondria to modulate mitochondrial quality and thereby mitochondrial bioenergetics. The clinical feature of mice carrying a mutation in CSB involves hearing loss, microglial activation, cachexia, and are mild compared to the catastrophic disease phenotype of CS in human patients. Our recent studies reveal novel complex features of the CSB mouse model, including elevated metabolic rate and altered autophagy. Mitochondrial content is increased in CSB-deficient cells, whereas autophagy is down-regulated, presumably as a result of defects in the recruitment of P62 and mitochondrial ubiquitination. CSB-deficient cells show increased free radical production and an accumulation of damaged mitochondria. Accordingly, treatment with the autophagic stimulators lithium chloride or rapamycin reverses the bioenergetic phenotype of CSB-deficient cells. Our data imply that CSB acts as an mtDNA damage sensor, inducing mitochondrial autophagy in response to stress, and that pharmacological modulators of autophagy are potential treatment options for this accelerated aging phenotype. Further, we generated a database dedicated to scoring diseases for mitochondrial involvement. Based on the signs and symptoms seen in CS and other DNA repair deficient disorders like AT and XPA, we have classified these disorders as likely having a mitochondrial component. In future studies, we plan to investigate whether the diet can ameliorate some of the defects observed in CSB mice.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
Application #
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
National Institute on Aging
Zip Code
Fang, Evandro Fei; Scheibye-Knudsen, Morten; Chua, Katrin F et al. (2016) Nuclear DNA damage signalling to mitochondria in ageing. Nat Rev Mol Cell Biol 17:308-21
Iyama, Teruaki; Lee, Sook Y; Berquist, Brian R et al. (2015) CSB interacts with SNM1A and promotes DNA interstrand crosslink processing. Nucleic Acids Res 43:247-58
Scheibye-Knudsen, Morten; Fang, Evandro F; Croteau, Deborah L et al. (2015) Protecting the mitochondrial powerhouse. Trends Cell Biol 25:158-70
Scheibye-Knudsen, Morten; Mitchell, Sarah J; Fang, Evandro F et al. (2014) A high-fat diet and NAD(+) activate Sirt1 to rescue premature aging in cockayne syndrome. Cell Metab 20:840-55
Scheibye-Knudsen, Morten; Fang, Evandro Fei; Croteau, Deborah L et al. (2014) Contribution of defective mitophagy to the neurodegeneration in DNA repair-deficient disorders. Autophagy 10:1468-9
Fang, Evandro Fei; Scheibye-Knudsen, Morten; Brace, Lear E et al. (2014) Defective mitophagy in XPA via PARP-1 hyperactivation and NAD(+)/SIRT1 reduction. Cell 157:882-96
Aamann, Maria D; Muftuoglu, Meltem; Bohr, Vilhelm A et al. (2013) Multiple interaction partners for Cockayne syndrome proteins: implications for genome and transcriptome maintenance. Mech Ageing Dev 134:212-24
Scheibye-Knudsen, Morten; Croteau, Deborah L; Bohr, Vilhelm A (2013) Mitochondrial deficiency in Cockayne syndrome. Mech Ageing Dev 134:275-83
Scheibye-Knudsen, Morten; Scheibye-Alsing, Karsten; Canugovi, Chandrika et al. (2013) A novel diagnostic tool reveals mitochondrial pathology in human diseases and aging. Aging (Albany NY) 5:192-208
Wilson 3rd, David M; Bohr, Vilhelm A (2013) Special issue on the segmental progeria Cockayne syndrome. Mech Ageing Dev 134:159-60

Showing the most recent 10 out of 24 publications