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 (DDR) is usually just regarded as an apoptotic trigger. However, growing evidence points to mitochondrial factors modulating nuclear functions. Remarkably, after DNA damage, cytochrome c (Cc) interacts in the cell nucleus with a variety of well-known histone chaperones, whose activity is competitively inhibited by the hemeprotein. As nuclear Cc 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 Cc 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, Cc may have a major regulatory role in DNA repair by fine-tuning nucleosome assembly activity and likely nuclear condensate formation.

The Histone Chaperones SET/TAF‐1β and NPM1 Exhibit Conserved Functionality in Nucleosome Remodeling and Histone Eviction in a Cytochrome c‐Dependent Manner

“…In addition, C c has been shown to be released from mitochondria and translocate into the nucleus under DNA damage conditions. [ 6 , 16 ] Although the nuclear role of C c is not fully understood, it has recently been shown that following DNA breaks, C c specifically interacts with SET/TAF‐Iβ, [ 6a ] and NAP1‐Related Protein 1 (NRP1), [ 6b ] a plant homologous of SET/TAF‐Iβ, acting as a histone chaperone inhibitor. Therefore, we decided to include C c in our single‐molecule kinetic experiments to challenge the relevance of the chaperone activities reported in Figure 3 .…”

De novo sequencing and construction of a unique antibody for the recognition of alternative conformations of cytochromecin cells

“…The translocation of cyt c to the nucleus was also reported after the induction of DNA damage and after treatment with proapoptotic agents, although there is no information regarding cyt c conformation ( 44 – 47 ). The functions of accumulated cyt c in the nucleus following apoptotic stimuli are related to nuclear pyknosis, DNA fragmentation, and chromatin remodeling ( 44 , 45 ).…”

“…It was previously shown that cyt c interacts with several histone chaperones, as is the case for the oncoprotein SET/TAF-Iβ. This interaction impairs the histone chaperone activity and prevents the formation of the core histone complex ( 46 – 48 ). These results suggest a wider role of cyt c in DNA damage response independent caspase activation.…”