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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 (Cc) interacts in the cell nucleus with a variety of well‐known histone chaperones, whose activity is competitively inhibited by the haem protein. 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.
Highlights
Cytochrome c and chromatin condensatesWhen mitochondrial cytochrome c (Cc) reaches the nucleus upon DNA damage, the hemeprotein binds to SET/template-activating factor (TAF)-Ib and competes with histones for binding to the chaperone [31]
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
Under DNA damage, cytochrome c (Cc) migrates from mitochondria to the nucleus, where it interacts with SET/template-activating factor (TAF)-Ib and impairs its nucleosome assembly activity [31]
Summary
When mitochondrial Cc reaches the nucleus upon DNA damage, the hemeprotein binds to SET/TAF-Ib and competes with histones for binding to the chaperone [31] This results in inhibition of the nucleosome assembly/disassembly activity of SET/ TAF-Ib, directly affecting its function on chromatin dynamics [31]. The hemeprotein could regulate the histone chaperone activity of ANP32B, as already described for SET/TAF-Ib and NRP1 [28,31,132,159] Within this context, Cc in the nucleus acquires a major regulatory role in the DNA repair process by fine-tuning the nucleosome assembly activity of histone chaperones. Experiments analysing general stress response pathways suggest a role for these proteins in the DDR [184] Despite their DNA damage-induced chromatin-binding ability, hnRNP C1/C2 are not actively recruited to the sites of DNA breaks [186]. To the above-described NCL:Cc complex, the DNA damage implications of the hnRNP C1/C2:Cc complexes are not fully understood yet
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