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 or OGD exposure, similar to inhibition of PAR
formation by the PARP inhibitor, DPQ.  Whereas, the catalytically
null variant Iduna C60A, or the PAR binding mutant Iduna Y156A and R157A
(YRAA) was ineffective in ubiquitinating histone H1.2 and preventing the
reduction in cytosolic histone H1.2 levels and PAR translocation from the
nucleus to the cytosol. Histone H1.2 heterozygote and homozygote knockout
mice exhibited reduced infarct volume 24 hrs post middle cerebral artery
occlusion (MCAO) and showed better recovery in motor deficits than
wildtype littermates at day 3 and/or day 7 post MCAO. 
Collectively, these findings reveal histone H1.2 as the key carrier of PAR
out of the nucleus to the cytosol where it participates in the next step
of the parthanatic cell death cascade.