Depletion of nuclear histone H2A variants is associated with chronic DNA damage signaling upon drug-evoked senescence of human somatic cells

Mary F Lopez,David Sarracino,Maryann Vogelsang,Glenn Geesman,Alejandra Garces,Victoria V Lunyak,Augusto Valderrama,James Tollervey,Bryan Krastins,Amol Prakash,I King Jordan

doi:10.18632/aging.100507

Abstract

Cellular senescence is associated with global chromatin changes, altered gene expression, and activation of chronic DNA damage signaling. These events ultimately lead to morphological and physiological transformations in primary cells. In this study, we show that chronic DNA damage signals caused by genotoxic stress impact the expression of histones H2A family members and lead to their depletion in the nuclei of senescent human fibroblasts. Our data reinforce the hypothesis that progressive chromatin destabilization may lead to the loss of epigenetic information and impaired cellular function associated with chronic DNA damage upon drug-evoked senescence. We propose that changes in the histone biosynthesis and chromatin assembly may directly contribute to cellular aging. In addition, we also outline the method that allows for quantitative and unbiased measurement of these changes.

Highlights

Functional differences between the cells in an organism are defined by epigenetic factors and epigenetic programs, which are critical for the preservation of functional integrity of the cellular phenotypes [1,2,3]
Senescence is triggered by various cellular stresses that result in genomic lesions and activation of chronic DNA damage signaling
Cycling early passage diploid HCA2 fibroblasts were cultivated as outlined in Materials and Methods Section, and treated with the chemomimicking agent, bleomycin (50 μg/ml), for 3 h to generate conditions of acute DNA damage

Summary

Introduction

Functional differences between the cells in an organism are defined by epigenetic factors and epigenetic programs, which are critical for the preservation of functional integrity of the cellular phenotypes [1,2,3] With aging, such “epigenetic memory” of the cellular identity goes awry, contributing to the deterioration of the specificity of transcriptional programs and fidelity of genome maintenance [4,5,6]. These events have a devastating consequence on tissue and organ homeostasis at both the cellular and organismal level [6, 7]. A dynamic balance between these two radically different chromatin compaction states is at the very core of the high-level nuclear chromatin organization (nuclear architecture), and www.impactaging.com

Methods

Results

Conclusion