Regulatory network built by Cytochrome c with Histone Chaperones in response to DNA damage

Abstract

The maintenance of genome integrity is a critical process for cell life. To face DNA lesions, living beings have developed a complex network called DNA damage response (DDR), which encompasses an intricate phosphorylation signalling cascade, enabling a quick DNA damage repair. To control this signalling cascade and to avoid an illegitimate activation, this network is tightly regulated by protein phosphatases, such as Protein Phosphatase 2A (PP2A). Moreover, histone chaperones assist the DNA repair mechanisms altering chromatin dynamics through their nucleosome assembly activity. Recent studies have reported that the mitochondrial respiratory protein cytochrome c is promptly translocated into the cell nucleus upon DNA damage, where it interacts with several histone chaperones. Within this context, the role of nuclear cytochrome c has been partially disclosed. Here, we have delved into the functional consequences of the novel DNA damage-induced complex formed by cytochrome c with the histone chaperones ANP32A and ANP32B. Strikingly, the heme protein impairs the PP2A inhibitory effect exerted by the histone chaperones ANP32A, ANP32B and SET/TAF-I. Furthermore, biophysical and structural approaches have been used to characterize the cytochrome c complex with ANP32A and ANP32B and to unveil the molecular mechanism underlying the cytoplasmic accumulation of ANP32B upon its phosphorylation. In addition, we have extended our knowledge on the histone chaperone regulation in the DDR by studying the Arabidopsis thaliana complex between cytochrome c and NRP1, a SET/TAF-I analogous. Herein we propose a novel standpoint about DDR regulation, in which cytochrome c exerts a modulating role on such signalling cascade through its interaction with histone chaperones, both by tuning their nucleosome assembly and PP2A inhibitory activity.