Cockayne syndrome (CS) is a devastating autosomal recessive disease characterized by neurodegeneration, cachexia, and accelerated aging. In CS cells, there are deficiencies in the repair of oxidative DNA damage in both nuclear and mitochondrial DNA, and this may contribute to disease features. Previously, we demonstrated that the CSB protein interacts with PARP1, a protein involved in the early steps of DNA DNA damage repair, and that these two proteins cooperate in the cellular responses to oxidative stress. PARP1 catalyzes PolyADP-ribosylation, PAR, on proteins and DNA in response to DNA damage. Thus, we speculated that loss of CSB may cause alterations in PAR accumulation which may alter chromatin status. To investigate PAR and chromatin we used ADPr-ChAP (ADP-ribose-chromatin affinity purification). We demonstrated that PAR was preferentially enriched at transcription start sides in CSB-deficient cells and further that this correlated with depletion of the heterochromatin marker, H3K9me3. We went on to show that SETDB1, a H3K9me3-specific methyltransferase, was downregulated in CSB-deficient cells. After restoration of SETDB1 expression in CSB-deficient cells, CSB-dependent mitochondrial dysfunction was partially rescued. Our results suggest that chromatin remodeling is a common feature found in premature aging syndromes. Previously, we generated a database dedicated to scoring diseases for mitochondrial involvement (www.mitodb.com). Based on the signs and symptoms seen in CS, we classified CS as likely having a mitochondrial component. We have developed the concept of nuclear-to-mitochondrial signaling as a framework to understand how defects in nuclear DNA can impinge upon mitochondrial function. In that regard, PARP1 metabolizes NAD+, and consequently, in target tissues like the brain, we find lower levels of NAD+, which may be contributing to mitochondrial dysfunction and CS pathology, including its severe early onset neurodegeneration. The clinical presentation 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. We speculate that the mitochondrial abnormalities are caused by decreased activation of the NAD+-SIRT1-PGC-1alpha axis triggered by persistent activation of the DNA damage sensor PARP-1. This leads to mitochondrial membrane hyper-polarization, PINK1 cleavage, and defective mitophagy. These findings underscore the importance of mitophagy in promoting a healthy pool of mitochondria and further in preventing neurodegeneration and premature aging. As mentioned above, one of the consistently observed features in CS patients is progressive and profound hearing loss. Thus, we have ongoing studies in the lab designed to characterize hearing defects in CS mice. Importantly, we find progressive hearing loss in CSA and CSB mice. Since mitochondrial dysfunction is often associated with hearing defects and we showed previously that NAD supplementation can improve mitophagy and mitochondrial physiology in cell-based models, we are testing whether NAD supplementation can ameliorate hearing loss in mice.
| Lee, Ju Yeon; Lake, Robert J; Kirk, Jaewon et al. (2017) NAP1L1 accelerates activation and decreases pausing to enhance nucleosome remodeling by CSB. Nucleic Acids Res 45:4696-4707 |
| Fivenson, Elayne M; Lautrup, Sofie; Sun, Nuo et al. (2017) Mitophagy in neurodegeneration and aging. Neurochem Int 109:202-209 |
| Karikkineth, Ajoy C; Scheibye-Knudsen, Morten; Fivenson, Elayne et al. (2017) Cockayne syndrome: Clinical features, model systems and pathways. Ageing Res Rev 33:3-17 |
| 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 |
| Scheibye-Knudsen, Morten; Tseng, Anne; Borch Jensen, Martin et al. (2016) Cockayne syndrome group A and B proteins converge on transcription-linked resolution of non-B DNA. Proc Natl Acad Sci U S A 113:12502-12507 |
| Scheibye-Knudsen, Morten; Fang, Evandro F; Croteau, Deborah L et al. (2015) Protecting the mitochondrial powerhouse. Trends Cell Biol 25:158-70 |
| 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; 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 20:840-855 |
| 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 157:882-896 |
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