Mitochondrial cytochrome c shot towards histone chaperone condensates in the nucleus

Abstract

Despite mitochondria being key for the control of cell homeostasis and fate, their role in DNA damage response is usually just regarded as an apoptotic trigger. However, growing evidence points to mitochondrial factors modulating nuclear functions. Remarkably, after DNA damage, cytochrome c (C c) interacts in the cell nucleus with a variety of well‐known histone chaperones, whose activity is competitively inhibited by the haem protein. As nuclear C c inhibits the nucleosome assembly/disassembly activity of histone chaperones, it might indeed affect chromatin dynamics and histone deposition on DNA. Several histone chaperones actually interact with C c Lys residues through their acidic regions, which are also involved in heterotypic interactions leading to liquid–liquid phase transitions responsible for the assembly of nuclear condensates, including heterochromatin. This relies on dynamic histone–DNA interactions that can be modulated by acetylation of specific histone Lys residues. Thus, C c may have a major regulatory role in DNA repair by fine‐tuning nucleosome assembly activity and likely nuclear condensate formation.

Abstract

DNA damage induces liquid–liquid phase separation within DNA foci, thereby allowing repair mechanisms to access damaged sites. DNA damage also makes mitochondrial cytochrome c translocate to the nucleus to sequester histone chaperones, for example SET/TAF‐Iβ, and impair their functions. We thus hypothesize that the INHAT activity in chromatin remodelling might be inhibited, as SET/TAF‐Iβ is a component of the INHAT complex.