Inhibition of the PP2A activity by the histone chaperone ANP32B is long-range allosterically regulated by respiratory cytochrome c

• Published in: Redox biology Vol. 43; p. 101967
• Main Authors: Rivero-Rodríguez, Francisco, Díaz-Quintana, Antonio, Velázquez-Cruz, Alejandro, González-Arzola, Katiuska, Gavilan, Maria P., Velázquez-Campoy, Adrián, Ríos, Rosa M., De la Rosa, Miguel A., Díaz-Moreno, Irene
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.07.2021; Elsevier
• Subjects: Cell Nucleus; Cytochrome c; Cytochromes c; DNA Damage; Histone chaperone; Histone Chaperones; Molecular dynamics; Nuclear magnetic resonance; Protein Phosphatase 2; Protein-protein interactions; Research Paper; Cytochrome c; Histone chaperone; Molecular dynamics; Nuclear magnetic resonance; Protein-protein interactions
• ISSN: 2213-2317; 2213-2317
• DOI: 10.1016/j.redox.2021.101967

Repair of injured DNA relies on nucleosome dismantling by histone chaperones and de-phosphorylation events carried out by Protein Phosphatase 2A (PP2A). Typical histone chaperones are the Acidic leucine-rich Nuclear Phosphoprotein 32 family (ANP32) members, e.g. ANP32A, which is also a well-known PP2A inhibitor (a.k.a. I1PP2A). Here we report the novel interaction between the endogenous family member B—so-called ANP32B—and endogenous cytochrome c in cells undergoing camptothecin-induced DNA damage. Soon after DNA lesions but prior to caspase cascade activation, the hemeprotein translocates to the nucleus to target the Low Complexity Acidic Region (LCAR) of ANP32B; in a similar way, our group recently reported that the hemeprotein targets the acidic domain of SET/Template Activating Factor-Iβ (SET/TAF-Iβ), which is another histone chaperone and PP2A inhibitor (a.k.a. I2PP2A). The nucleosome assembly activity of ANP32B is indeed unaffected by cytochrome c binding. Like ANP32A, ANP32B inhibits PP2A activity and is thus herein referred to as I3PP2A. Our data demonstrates that ANP32B-dependent inhibition of PP2A is regulated by respiratory cytochrome c, which induces long-distance allosteric changes in the structured N-terminal domain of ANP32B upon binding to the C-terminal LCAR. In agreement with the reported role of PP2A in the DNA damage response, we propose a model wherein cytochrome c is translocated from the mitochondria into the nucleus upon DNA damage to modulate PP2A activity via its interaction with ANP32B. •Respiratory cytochrome c interacts with ANP32B under DNA damage in the nucleus.•Cytochrome c binding to ANP32B LCAR restores ANP32B-mediated PP2A inhibition.•Cytochrome c emerges as a DNA Damage Response regulator.