Abstract
BackgroundExtensive DNA damage leads to apoptosis. Histones play a central role in DNA damage sensing and may mediate signals of genotoxic damage to cytosolic effectors including mitochondria.Methodology/Principal FindingsWe have investigated the effects of histones on mitochondrial function and membrane integrity. We demonstrate that both linker histone H1 and core histones H2A, H2B, H3, and H4 bind strongly to isolated mitochondria. All histones caused a rapid and massive release of the pro-apoptotic intermembrane space proteins cytochrome c and Smac/Diablo, indicating that they permeabilize the outer mitochondrial membrane. In addition, linker histone H1, but not core histones, permeabilized the inner membrane with a collapse of the membrane potential, release of pyridine nucleotides, and mitochondrial fragmentation.ConclusionsWe conclude that histones destabilize the mitochondrial membranes, a mechanism that may convey genotoxic signals to mitochondria and promote apoptosis following DNA damage.
Highlights
The genome is continuously exposed to external and internal genotoxic agents that can damage the DNA and lead to loss of genetic information
We conclude that histones destabilize the mitochondrial membranes, a mechanism that may convey genotoxic signals to mitochondria and promote apoptosis following DNA damage
The first level of DNA compaction consists in the assembly of arrays of nucleosomes composed of two copies of each of the core histones H2A, H2B, H3 and H4, around which an about 147-bp long stretch of DNA is wrapped into nearly two superhelical turns
Summary
The genome is continuously exposed to external and internal genotoxic agents that can damage the DNA and lead to loss of genetic information. Defects in the molecular switches between DNA repair and apoptosis are likely to contribute to degenerative disorders and tumor formation. DNA damage sensing and repair tailoring remains incompletely understood at molecular level. The first level of DNA compaction consists in the assembly of arrays of nucleosomes composed of two copies of each of the core histones H2A, H2B, H3 and H4, around which an about 147-bp long stretch of DNA is wrapped into nearly two superhelical turns. Histones play a central role in DNA damage sensing and may mediate signals of genotoxic damage to cytosolic effectors including mitochondria
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