Cockayne syndrome group B deficiency reduces H3K9me3 chromatin remodeler SETDB1 and exacerbates cellular aging
Copyright policy )Cockayne syndrome group B deficiency reduces H3K9me3 chromatin remodeler SETDB1 and exacerbates cellular aging
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.
- National Institute of Health Pakistan
- University of Copenhagen Denmark
- University of Copenhagen Denmark
- University of Copenhagen Denmark
- KOBENHAVNS UNIVERSITET Denmark
Poly Adenosine Diphosphate Ribose, DNA Helicases, DNA, Histone-Lysine N-Methyltransferase, Methyltransferases, Fibroblasts, NAD, Chromatin, Mitochondria, Histones, DNA Repair Enzymes, Gene Expression Regulation, Mutation, Humans, Poly(ADP-ribose) Polymerases, Cockayne Syndrome, Poly-ADP-Ribose Binding Proteins, Cellular Senescence, Cell Line, Transformed, DNA Damage
Poly Adenosine Diphosphate Ribose, DNA Helicases, DNA, Histone-Lysine N-Methyltransferase, Methyltransferases, Fibroblasts, NAD, Chromatin, Mitochondria, Histones, DNA Repair Enzymes, Gene Expression Regulation, Mutation, Humans, Poly(ADP-ribose) Polymerases, Cockayne Syndrome, Poly-ADP-Ribose Binding Proteins, Cellular Senescence, Cell Line, Transformed, DNA Damage
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