Beyond a platform protein for the degradosome assembly: The Apoptosis-Inducing Factor as an efficient nuclease involved in chromatinolysis

Abstract

The Apoptosis-Inducing Factor (AIF) is a moonlighting flavoenzyme involved in the assembly of mitochondrial respiratory complexes in healthy cells, but also able to trigger DNA cleavage and parthanatos. Upon apoptotic-stimuli, AIF redistributes from the mitochondria to the nucleus, where upon association with other proteins such as endonuclease CypA and histone H2AX, it is proposed to organize a DNA-degradosome complex. In this work, we provide evidence for the molecular assembly of this complex as well as for the cooperative effects among its protein components to degrade genomic DNA into large fragments. We have also uncovered that AIF has nuclease activity that is stimulated in the presence of either Mg2+ or Ca2+. Such activity allows AIF by itself and in cooperation with CypA to efficiently degrade genomic DNA. Finally, we have identified TopIB and DEK motifs in AIF as responsible for its nuclease activity. These new findings point, for the first time, to AIF as a nuclease able to digest nuclear dsDNA in dying cells, improving our understanding of its role in promoting apoptosis and opening paths for the development of new therapeutic strategies.

The Mechanisms of Regulated Cell Death: Structural and Functional Proteomic Pathways Induced or Inhibited by a Specific Protein—A Narrative Review

“…But the excessive PARP-1 activation leads to an intrinsic CD program, PARP-1 is translocated from the nucleus to the cytosol and interacts with the mitochondrial outer surface, where the release of mitochondrial Apoptosis-Inducing Factor (AIF) is induced [ 64 , 65 ]. The redox regulation (NADH-dependent oxidoreductase) of AIF [ 66 ] induces its dimerization and the formation of degradosome assemblies with histones and cyclophilin A [ 67 ] to exert the endonuclease activity and subsequent DNA cleavage. AIF has a high affinity for binding to poly (ADP-ribose), this union is critical and key in the process of parthanatos both in vitro and in vivo, since AIF is released from the mitochondria and translocated to the nucleus, where it triggers pyknosis and DNA fragmentation [ 61 ].…”

A Review of the Current State of Magnetic Force Microscopy to Unravel the Magnetic Properties of Nanomaterials Applied in Biological Systems and Future Directions for Quantum Technologies

“…For this reason, it is necessary to carry out more research on this topic by designing customized ultrasensitive detection strategies at the single-molecule level. The gathered knowledge could serve not only to gain more insights according to the sequential binding and location of protein regulators on DNA strands [ 162 ], which regulates the organism gene expression [ 163 ] or the DNA degradation beyond the proteasome activation [ 164 ], but also to optimize those industrial technologies related to DNA, such as clustered regularly interspaced short palindromic repeat-associated protein 9 (CRISPR-Cas9), which enables edit-specific genes in an organism that can be exploited in drug delivery [ 165 ] or agricultural biotechnology [ 166 ], among others.…”

Progress and Prospects of Gene Editing in Pluripotent Stem Cells

“…First, PSCs possess a superior ability to repair DNA damages by expressing abundant mismatch repair proteins or avoiding error-prone repair pathways [ 39 , 40 , 41 , 42 ]. The high DNA repair capability also suggests the fast removal of the DSB marker γ-H2AX, thus antagonizing its association with apoptosis-inducing factor (AIF) for the formation of the “degradosome” that leads to chromatin remodeling and large-scale DNA fragmentation [ 43 , 44 ]. Second, once the level of DNA damage accumulates over a threshold, PSCs are highly prone to apoptosis, eliminating themselves from the whole population.…”