AI Article Synopsis
- Cockayne syndrome is an accelerated aging disorder linked to mutations in the CSA or CSB genes, leading to persistent DNA damage and mitochondrial dysfunction.
- In CSB-deficient cells, poly (ADP ribose) (PAR) accumulates at transcription start sites, causing a decrease in heterochromatin and a reduction in specific methyltransferases like SUV39H1 and SETDB1.
- Enhancing SETDB1 expression in these cells reduces PAR levels and restores normal mitochondrial function, indicating that CSB defects disrupt heterochromatin and contribute to cell dysfunction.
Article Abstract
Cockayne syndrome is an accelerated aging disorder, caused by mutations in the CSA or CSB genes. In CSB-deficient cells, poly (ADP ribose) polymerase (PARP) is persistently activated by unrepaired DNA damage and consumes and depletes cellular nicotinamide adenine dinucleotide, which leads to mitochondrial dysfunction. Here, the distribution of poly (ADP ribose) (PAR) was determined in CSB-deficient cells using ADPr-ChAP (ADP ribose-chromatin affinity purification), and the results show striking enrichment of PAR at transcription start sites, depletion of heterochromatin and downregulation of H3K9me3-specific methyltransferases SUV39H1 and SETDB1. Induced-expression of SETDB1 in CSB-deficient cells downregulated PAR and normalized mitochondrial function. The results suggest that defects in CSB are strongly associated with loss of heterochromatin, downregulation of SETDB1, increased PAR in highly-transcribed regions, and mitochondrial dysfunction.
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Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6895253 | PMC |
| http://dx.doi.org/10.1093/nar/gkz568 | DOI Listing |
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