Abstract
Eukaryotic genomes are wrapped around nucleosomes and organized into different levels of chromatin structure. Chromatin organization has a crucial role in regulating all cellular processes involving DNA-protein interactions, such as DNA transcription, replication, recombination and repair. Histone post-translational modifications (HPTMs) have a prominent role in chromatin regulation, acting as a sophisticated molecular code, which is interpreted by HPTM-specific effectors. Here, we review the role of histone lysine methylation changes in regulating the response to radiation-induced genotoxic damage in mammalian cells. We also discuss the role of histone methyltransferases (HMTs) and histone demethylases (HDMs) and the effects of the modulation of their expression and/or the pharmacological inhibition of their activity on the radio-sensitivity of different cell lines. Finally, we provide a bioinformatic analysis of published datasets showing how the mRNA levels of known HMTs and HDMs are modulated in different cell lines by exposure to different irradiation conditions.
Highlights
The first and basic level of chromatin organization consists in the wrapping of genomic DNA around histone octamers forming the nucleosomes (Luger et al, 2012)
The canonical lysine methylation sites are found on histone H3 tail at lysine 4 (H3K4), lysine 9 (H3K9), lysine 27 (H3K27), lysine 36 (H3K36) and lysine 79 (H3K79), and on histone H4 tail at lysine 20 (H4K20) (Husmann and Gozani, 2019)
Two annotated protein domains carry out lysine methylation: the SET domain (named after three Drosophila melanogaster proteins originally recognized as containing this domain, namely Su(var)3–9, Enhancer of Zeste and Trithorax), and the sevenbeta-strand (7βS) domain (Husmann and Gozani, 2019)
Summary
The first and basic level of chromatin organization consists in the wrapping of genomic DNA around histone octamers forming the nucleosomes (Luger et al, 2012). Histone tails, which protrude from the nucleosome core, are the target of a plethora of post-translational chemical modifications, such as: acetylation, methylation, phosphorylation, ubiquitylation, sumoylation and ADP-ribosylation (Campos and Reinberg, 2009; Bannister and Kouzarides, 2011) These Histone Post-Translational Modifications (HPTMs) form a sophisticated code of signals, known as histone code, which regulates the interactions of the genome with very important cellular effectors involved in several biological processes. We will review recent progress in this field, focusing on histone lysine methylation changes associated with the genotoxic damage induced by ionizing radiation (IR) and on their role in triggering damage checkpoint and DNA repair in mammalian cells. Genome integrity is continuously checked by the DDR, a series of complex interacting cellular pathways triggered by the sensor protein complexes located at the genomic lesions (Polo and Jackson, 2011)
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