Response to DNA damage: The dual role of extramitochondrial cytochrome C

Living beings are continuously exposed to harmful agents, both exogenous (ultraviolet radiation, polluting gases, etc.) and endogenous (secondary products of cellular metabolism) that can affect DNA integrity. That's why cells are endowed with a series of molecular mechanisms whose purpose is to identify and signpost possible damage to the genetic material for speedy repair. These mechanisms are precisely regulated because they are key to cell survival. In extreme situations of massive and irreparable damage, cells enter a phase of controlled dismantling called "programmed cell death". Among the events that take place during this process is the massive delivery to the cytoplasm of a mitochondrial protein called cytochrome C. Under homeostatic conditions, this protein plays a role in energy metabolism within the mitochondria. However, in situations of irreparable damage, it directs the controlled and orchestrated destruction of the cell from the cytoplasm.

The authors of this paper suggest that extramitochondrial cytochrome C plays a dual role in response to cell damage. In the initial stages of damage, a limited amount of cytochrome C is able to reach the cell nucleus without accumulating in the cytoplasm and, therefore, without triggering programmed cell death. Once in the nucleus, cytochrome C interacts with the protein ANP32B, a histone chaperone that helps maintain DNA structure and inhibits the activity of the enzyme (phosphatase) PP2A, a major promoter of DNA damage repair. Thus, cytochrome C "hijacks" ANP32B as a means of activating PP2A and facilitating DNA repair. When damage to the genetic material cannot be repaired by the cellular mechanisms, cytochrome C "floods" both the cytoplasm and the nucleus, leading to the irremediable death of the cell. "What's the point of continuing to build a house that's going to be demolished?".

This project received funding from the Ramón Areces Foundation and the Spanish Association Against Cancer (AECC), as well as from the Spanish Government and the Andalusian Regional Government.

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