Biological function and regulation of histone 4 lysine 20 methylation in DNA damage response

Abstract

Cells are often under attack from various DNA-damaging agents. Accurate repair is required to protect cells from the genome instability induced by DNA lesions. DNA damage response (DDR) signaling involves sensitizing, transmitting, and repairing different types of damage within chromatin complexes. Chromatin is a highly ordered complex packed with repeating units of nucleosomes and linker DNA sequences. Chromatin structure, gene transcription, and various biological processes are regulated by histone post-translational modifications (PTMs), including acetylation, methylation, phosphorylation, and ubiquitylation. Of these, the involvement of lysine methylation, regulated by numerous lysine methyltransferases and demethylases, in the DDR has been extensively explored. In particular, histone 4 lysine 20 methylation is one of the most essential histone PTMs for biological processes and ensures genome integrity. In this review, we summarize the dynamics and modulations of histone lysine methylation during the DDR. We also comprehensively describe the functions, mechanisms, and regulation of H4K20 methylation and its modifying enzymes in response to DNA damage.

The chromatin network helps prevent cancer-associated mutagenesis at transcription-replication conflicts

“…Consistent with previous data 26 , SWI/SNF complex factors SMARCA4 and ARID1B were clustered together and enriched at sequences with high SNV signatures driven by APOBEC mutagenesis and HR deficiencies and sequences with indel patterns observed at sites of head-on TRCs. In contrast, SMARCA5 and MTA1/2/3 strongly associated with APOBEC mutagenesis, MMR deficiencies and topoisomerase 1/2A-dependent mutagenesis, as also observed for H4K20me1, a histone modification tightly associated with DNA repair and replication 53 . Other factors including YY1, an INO80 subunit, or SIN3B HDACs correlated with APOBEC-induced mutagenesis, MMR deficiencies, DNA replication slippage and different patterns of unknown etiology.…”

Histone 4 lysine 20 tri-methylation: a key epigenetic regulator in chromatin structure and disease

“…In a homeostatic cell, the levels of H4K20me3 vary depending on the cell cycle stage ( Figure 6 ) and on the levels of H4K20me1/2. In resting cells in G1 or G0 H4K20me3 is high in heterochromatic regions, H4K20me2 is present throughout the genome, and H4K20me1 is restricted to specific genes ( Kohi et al, 2022 ). In early G1, H4K20me1 is reduced as it gets converted to the di- and tri-methylated form (H4K20me2/3) ( Kohi et al, 2022 ).…”

“…In resting cells in G1 or G0 H4K20me3 is high in heterochromatic regions, H4K20me2 is present throughout the genome, and H4K20me1 is restricted to specific genes ( Kohi et al, 2022 ). In early G1, H4K20me1 is reduced as it gets converted to the di- and tri-methylated form (H4K20me2/3) ( Kohi et al, 2022 ). Additionally, due to proteolytic degradation of SET8 during G1, new H4K20me1 modifications are greatly reduced ( Kohi et al, 2022 ).…”

“…In early G1, H4K20me1 is reduced as it gets converted to the di- and tri-methylated form (H4K20me2/3) ( Kohi et al, 2022 ). Additionally, due to proteolytic degradation of SET8 during G1, new H4K20me1 modifications are greatly reduced ( Kohi et al, 2022 ). In S phase, during DNA replication when cells are incorporating new histone 4 molecules, very little H4K20me1 is present due to limited SET8 methyltransferase levels ( Kohi et al, 2022 ).…”

“…Additionally, due to proteolytic degradation of SET8 during G1, new H4K20me1 modifications are greatly reduced ( Kohi et al, 2022 ). In S phase, during DNA replication when cells are incorporating new histone 4 molecules, very little H4K20me1 is present due to limited SET8 methyltransferase levels ( Kohi et al, 2022 ). However, at the end of S phase, SET8 expression is stabilized resulting in H4K20me1 establishment on most of the new H4 molecules ( Kohi et al, 2022 ).…”