Apoptotic Phosphorylation of Histone H2B Is Mediated by Mammalian Sterile Twenty Kinase

Abstract

DNA in eukaryotic cells is associated with histone proteins; hence, hallmark properties of apoptosis, such as chromatin condensation, may be regulated by posttranslational histone modifications. Here we report that phosphorylation of histone H2B at serine 14 (S14) correlates with cells undergoing programmed cell death in vertebrates. We identify a 34 kDa apoptosis-induced H2B kinase as caspase-cleaved Mst1 (mammalian sterile twenty) kinase. Mst1 can phosphorylate H2B at S14 in vitro and in vivo, and the onset of H2B S14 phosphorylation is dependent upon cleavage of Mst1 by caspase-3. These data reveal a histone modification that is uniquely associated with apoptotic chromatin in species ranging from frogs to humans and provide insights into a previously unrecognized physiological substrate for Mst1 kinase. Our data provide evidence for a potential apoptotic "histone code."

Regulation of histone modification and chromatin structure by the p53–PADI4 pathway

“…Histone H2AX is phosphorylated at serine 139 residue (γ-H2AX) on external damage, and recruits DNA repair complex to promote chromatin remodelling 31,32 . Recently, phosphorylation of serine 14 residue in H2B, which was induced on several apoptotic stimuli including DNA damage 33 , was proposed as a 'death code, but its physiological significance remains to be determined. Histone methylation, phosphorylation and acetylation are reversible processes that are regulated by histone-modifying enzymes 34 .…”

F-actin-binding domain of c-Abl regulates localized phosphorylation of C3G: role of C3G in c-Abl-mediated cell death

“…c-Abl induced cell death scored by pH2B(S14) positivity, an early marker for cell death (Cheung et al, 2003)-matched quantitation of apoptosis scored using morphological criteria ( Supplementary Figures 2a and b). Staurosporine treatment enhanced apoptosis in c-Abl-expressing cells concomitant with an increase in the number of p-C3G-stained cells and an increase in p-C3G and p-Abl levels ( Supplementary Figures 2c and d).…”

Prognostic significance of mammalian sterile20-like kinase 1 in colorectal cancer

“…11,12 Extensive studies to identify potential Mst1 substrates in the nucleus have led to identification of Histone H2B as a physiologic substrate for the catalytic domain of Mst1, the phosphorylation of which leads to chromatin condensation and apoptosis. 13 Based on its proposed function in apoptosis, Mst1 might play a tumor suppressor role in human cancers as has been suggested for its Drosophila homologs. [14][15][16][17] Nevertheless, there is no report on the biological significance of Mst1 expression in primary human cancer cells.…”