Histone H1.2 is translocated to mitochondria and associates with bak in bleomycin‐induced apoptotic cells

Abstract

Bleomycin induces single- and double-stranded breaks in DNA, with consequent mitochondrial membrane aberrations that lead to the apoptotic cell death. It is poorly understood how DNA damage-inducing apoptotic signals are transmitted to mitochondria, from which apoptotic factors are released into the cytoplasm. Here, we investigated the localization of histone H1.2 in the bleomycin-treated human squamous carcinoma SCCTF cells. The presence of DNA double-strand breaks in the bleomycin-treated cells was examined by Western analysis using antibody against phosphorylated histone H2AX (gamma-H2AX). Incubation of SCCTF cells for 48 h with 10 microM bleomycin induced apoptosis, as determined by cleavage of lamin B1 to 28 kDa fragment and DNA ladder formation. The mitochondrial permeabilization causing apoptotic feature was also detected with MitoCapture in the bleomycin-treated cells. Histone H1.2 was translocated from the nucleus to the mitochondria after treatment with bleomycin and co-localized with Bak in mitochondria. Our present results suggest that histone H1.2 plays an important role in transmitting apoptotic signals from the nucleus to the mitochondria following double-stranded breaks of DNA by bleomycin.

Regulation of stress-induced nuclear protein redistribution: a new function of Bax and Bak uncoupled from Bcl-xL

“…It was previously proposed that cytosolic H1.2 and NPM facilitate apoptosis through Bax/Bak. [13][14][15][16] Our finding that the H1 and NPM redistribution is mediated through Bax/Bak implies that Bax and Bak act upstream of H1.2 and NPM, and thus regulate the ability of these nuclear proteins to activate them. The role of nucleolin redistribution in response to stress signals is more enigmatic.…”

“…Apart from Bax and cytochrome c, other examples of such proteins include the nuclear proteins p53, 7,8 Nur77, 9 caspase-2, 10 nucleophosmin (NPM), 11,12 and histone H1.2. 13,14 During apoptosis, all these proteins migrate from the nucleus to the cytosol and/or to mitochondria, where they participate in crucial steps of apoptosis. The mechanisms underlying nuclear/cytoplasmic redistribution and particular apoptotic pathways involved remain to be elucidated.…”

“…17 A particular isoform of H1, H1.2, was found to co-localize with Bak and to contribute to cytochrome c release and apoptosis in a Bak-dependent manner. 13,14 Nucleolin is a nucleolar protein involved in chromatin remodeling, DNA recombination and replication, RNA transcription, rRNA processing and mRNA stabilization. 18,19 Under stress conditions such as herpes simplex virus type 1 infection 20 or DNA damage, 21 nucleolin redistributes from nucleoli to the nucleoplasm and to the cytosol.…”

Linker Histones Are Mobilized during Infection with Herpes Simplex Virus Type 1

“…Productive HSV-1 infection activates the cellular DNA damage response (49,64,66), and H1.2 has been reported to translocate to the cytoplasm following double-strand breaks (24,41). Mobilization of H1.2 during HSV-1 infection could therefore be the result of activation of DNA damage responses and subsequent release of H1.2.…”

H1 histone subtype constitution and phosphorylation state of the ageing cell system of human peripheral blood lymphocytes

“…One proposal is that H1 hyperphosphorylation itself might serve as a mitotic "trigger" and not the actual physical means for condensation (Roth and Allis, 1992 These data point towards the fact that specific H1 subtypes and their phosphorylation states may have specific functional roles in chromatin remodeling events which are responsible for transcriptional regulation that takes place during various biological processes such as development, differentiation, DNA repair (Downs et al, 2003), apoptosis (Konishi et al, 2003;Okamura et al, 2007) and lifespan (Barra et al, 2000).…”