Chromatin modifications and the DNA damage response to ionizing radiation

Abstract

In order to survive, cells have evolved highly effective repair mechanisms to deal with the potentially lethal DNA damage produced by exposure to endogenous as well as exogenous agents. Ionizing radiation exposure induces highly lethal DNA damage, especially DNA double-strand breaks (DSBs), that is sensed by the cellular machinery and then subsequently repaired by either of two different DSB repair mechanisms: (1) non-homologous end joining, which re-ligates the broken ends of the DNA and (2) homologous recombination, that employs an undamaged identical DNA sequence as a template, to maintain the fidelity of DNA repair. Repair of DSBs must occur within the natural context of the cellular DNA which, along with specific proteins, is organized to form chromatin, the overall structure of which can impede DNA damage site access by repair proteins. The chromatin complex is a dynamic structure and is known to change as required for ongoing cellular processes such as gene transcription or DNA replication. Similarly, during the process of DNA damage sensing and repair, chromatin needs to undergo several changes in order to facilitate accessibility of the repair machinery. Cells utilize several factors to modify the chromatin in order to locally open up the structure to reveal the underlying DNA sequence but post-translational modification of the histone components is one of the primary mechanisms. In this review, we will summarize chromatin modifications by the respective chromatin modifying factors that occur during the DNA damage response.

A Hormone–DNA Repair Circuit Governs the Response to Genotoxic Insult

“…Alternatively, the histone acetyltransferases CBP and p300, known AR coactivators, promote expression of the HR genes BRCA1 and RAD51 [55], indicating that AR likely utilizes a distinct cohort of cofactors to alter gene expression after DNA damage. Finally, post-translational modifications of nucleosomes are known to influence DDR [56], and it is also tempting to speculate that AR may be recruited to genes that promote DDR via altered histone modification. Combined, these collective studies strongly suggest that DNA damage-induced transcription factor activation plays a major role in DDR and the cellular response to genotoxic damage.…”

Pluripotent Stem Cells and DNA Damage Response to Ionizing Radiations

“…Double-stranded break (DSB) is the most lethal form of DNA damage, which is primarily repaired by non-homologous end joining (NHEJ) (62, 63). NHEJ can occur throughout the cell cycle – predominantly in G1 but also in the S and G2 phases when repair by homologous recombination (HR) is also possible.…”

Dynamics of chromatin accessibility and epigenetic state in response to UV damage

“…For example, the components of the ATP-dependent SWI-SNF chromatin remodeling complex BRG1 and BRM (also known as SMARCA4 and SMARCA2, respectively) have been implicated in the transcriptional regulation of UV-induced genes (Hassan et al, 2014;Zhang et al, 2014). Furthermore, many posttranslational histone modifications have been shown to be modulated during the cellular response to DNA damage (Corpet and Almouzni, 2009;Kumar et al, 2012;Li et al, 2014;Tjeertes et al, 2009). For example, following UV exposure, the histone acetyltransferase p300 (also known as EP300) is recruited close to the MMP-1 promoter, regulating MMP-1 transcription by its catalytic activity (Kim et al, 2009).…”