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.

• Authors: Jong-Hyuk Lee, Tyler G Demarest, Mansi Babbar, Edward W Kim, Mustafa N Okur, Supriyo De, Deborah L Croteau, Vilhelm A Bohr
• Journal: Nucleic acids research (Nucleic Acids Res) Vol. 47 Issue 16 Pg. 8548-8562 (09 19 2019) ISSN: 1362-4962 [Electronic] England
• PMID: 31276581 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)
• Copyright: Published by Oxford University Press on behalf of Nucleic Acids Research 2019.

Chemical References

• Chromatin
• ERCC8 protein, human
• Histones
• Poly-ADP-Ribose Binding Proteins
• Repressor Proteins
• Transcription Factors
• NAD
• Poly Adenosine Diphosphate Ribose
• DNA
• SUV39H1 protein, human
• Methyltransferases
• Protein Methyltransferases
• Histone-Lysine N-Methyltransferase
• SETDB1 protein, human
• Poly(ADP-ribose) Polymerases
• DNA Helicases
• ERCC6 protein, human
• DNA Repair Enzymes

Topics

• Cell Line, Transformed
• Cellular Senescence (genetics)
• Chromatin (chemistry, metabolism)
• Cockayne Syndrome (genetics, metabolism, pathology)
• DNA (genetics, metabolism)
• DNA Damage
• DNA Helicases (genetics, metabolism)
• DNA Repair Enzymes (genetics, metabolism)
• Fibroblasts (metabolism, pathology)
• Gene Expression Regulation
• Histone-Lysine N-Methyltransferase
• Histones (genetics, metabolism)
• Humans
• Methyltransferases (genetics, metabolism)
• Mitochondria (metabolism, pathology)
• Mutation
• NAD (metabolism)
• Poly Adenosine Diphosphate Ribose (metabolism)
• Poly(ADP-ribose) Polymerases (genetics, metabolism)
• Poly-ADP-Ribose Binding Proteins (genetics, metabolism)
• Protein Methyltransferases (genetics, metabolism)
• Repressor Proteins (genetics, metabolism)
• Signal Transduction
• Transcription Factors (genetics, metabolism)
• Transcription Initiation Site
• Transcription, Genetic