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

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.

SIRT6 Depletion Suppresses Tumor Growth by Promoting Cellular Senescence Induced by DNA Damage in HCC

“…In consistent with the previous reports that DNA damage is linked to altered cell cycle distribution[27] and histone loss[25, 26], our expression and cell cycle analyses showed that SIRT6 depletion downregulated histone-encoding genes and promoted altered cell cycle distribution. Change of the chromatin structure by downregulated histone levels could be a cause of cellular senescence[24].…”

“…Change of the chromatin structure by downregulated histone levels could be a cause of cellular senescence[24]. Downregulation of histone levels caused chromatin to be more open, which led to inappropriate access to DNA, disrupting transcriptional regulation and chromatin destabilization[24, 25]. Maintenance of the fundamental chromatin structure was reported to be important for delaying the aging process and overexpression of histones extends life span[42].…”

Common and distinct mechanisms of induced pulmonary fibrosis by particulate and soluble chemical fibrogenic agents

“…A recent finding reveals that acute DNA damage induced by bleomycin significantly increased the relative nuclear abundance of histone H2A family in primary human HCA2 fibroblasts (Lopez et al 2012). This observation indicates that fibrogenic agents may confer cytotoxicity through generating genotoxic effects, which is consistent with the previous finding that bleomycin exposure induced single- and double-strand DNA breaks, through which it resulted in cytotoxicity and cell death in the lungs (Huang et al 1981; Tounekti et al 1993).…”

Acute Genotoxic Stress-Induced Senescence in Human Mesenchymal Cells Drives a Unique Composition of Senescence Messaging Secretome (SMS)

“…SEN hADSCs were obtained by treating the hADSCs at PD9 with 50 µg/ml final concentration of bleomycin diluted from 10mg/ml bleomycin stock in complete xeno-free media for 2 hrs at 37°C as previously described (in [27,31] and shown schematically in Figure 2A). Following the treatment, the medium was aspirated, the cells were washed twice with PBS and fresh complete xeno-free media was replaced.…”