Histone H1.2 dependent translocation of poly (ADP-ribose) initiates parthanatos

Toxic cellular insults activate the nuclear protein poly (ADP-ribose) (PAR) polymerase-1 (PARP-1) to initiate parthanatos, a regulated cell death program. PAR acts as a death signal by translocating from the nucleus to the cytosol, where it activates the next steps in the parthanatic cell death cascade.  How PAR translocates from the nucleus to the cytosol is not known. Here, we show that PARylation and PAR binding to histone H1.2 enables it to act as a carrier, transporting PAR out of the nucleus to the cytosol. Knocking down the expression of histone H1.2 via CRISPR/Cas9 and knockout of histone H1.2 reduces the translocation of PAR to the cytosol after treatment of human cortical neurons with N-methyl-D-aspartate (NMDA) or following oxygen-glucose deprivation (OGD). The PAR-dependent E3 ubiquitin ligase, Iduna (RNF146) ubiquitinates PARylated H1.2. Overexpression of Iduna reduces the expression levels of cytosolic histone H1.2, preventing the translocation of PAR following NMDA o..., , # Histone H1.2 dependent translocation of poly (ADP-ribose) initiates parthanatos

Dataset DOI: [10.5061/dryad.6m905qgdg](https://doi.org/10.5061/dryad.6m905qgdg)

## Description of the data and file structure

In this study, we discovered how a molecule called poly(ADP-ribose) (PAR), which signals cells to die under toxic conditions, moves from the nucleus to the cytosol to trigger cell death. This form of cell death, known as parthanatos, is activated when the enzyme PARP-1 in the nucleus produces PAR. However, how PAR exits the nucleus was previously unknown. We found that a nuclear protein, histone H1.2, binds to and carries PAR out of the nucleus. When histone H1.2 was reduced or deleted in human neurons, PAR could no longer move to the cytosol after exposure to harmful stimuli such as NMDA or oxygen-glucose deprivation. We also showed that another protein, Iduna (RNF146), tags histone H1.2 with ubiquitin to control its movement and the release of PAR. In mice, deleting histone H1....,