Dot1/DOT1L catalyzes the methylation of histone H3 lysine 79 (H3K79), which regulates diverse cellular processes, such as development, reprogramming, differentiation, and proliferation. In regards to these processes, studies of Dot1/DOT1L-dependent H3K79 methylation have mainly focused on the transcriptional regulation of specific genes. Although the gene transcription mediated by Dot1/DOT1L during the cell cycle is not fully understood, H3K79 methylation plays a critical role in the progression of G1 phase, S phase, mitosis, and meiosis. This modification may contribute to the chromatin structure that controls gene expression, replication initiation, DNA damage response, microtubule reorganization, chromosome segregation, and heterochromatin formation. Overall, Dot1/DOT1L is required to maintain genomic and chromosomal stability. This review summarizes the several functions of Dot1/DOT1L and highlights its role in cell cycle regulation.

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Morin is a flavonoid isolated from certain fruits and Chinese herbs and is known to possess various medicinal properties. In this study, we investigated the anti-inflammatory effects of morin on lipopolysaccharide (LPS)-induced microglial activation, both in vitro and in vivo. We found that morin inhibited inducible nitric oxide synthase (iNOS) and pro-inflammatory cytokines in LPS-stimulated BV2 microglial cells. Furthermore, morin suppressed the microglial activation and cytokine expression in the brains of LPS-stimulated mice. Subsequent mechanistic studies revealed that morin inhibited the action of LPS-activated mitogen-activated protein kinases (MAPKs), protein kinase B (Akt) phosphorylation, nuclear factor-κB (NF-κB), and activating protein-1 (AP-1). Further, the phosphorylation and DNA binding activity of cAMP responsive element binding protein (CREB) was enhanced by morin. Moreover, morin suppressed the LPS-induced expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits, while it increased heme oxygenase-1 (HO-1) expression and nuclear factor erythroid 2-related factor 2 (Nrf2) activation. Therefore, our data suggest that morin exerts anti-inflammatory effects in LPS-stimulated microglia by downregulating MAPK and phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathways while upregulating protein kinase A (PKA)/CREB and Nrf2/HO-1 signaling pathways.

RAP80 localizes to sites of DNA insults to enhance the DNA-damage responses. Here we identify TRAIP/RNF206 as a novel RAP80-interacting protein and find that TRAIP is necessary for translocation of RAP80 to DNA lesions. Depletion of TRAIP results in impaired accumulation of RAP80 and functional downstream partners, including BRCA1, at DNA lesions. Conversely, accumulation of TRAIP is normal in RAP80-depleted cells, implying that TRAIP acts upstream of RAP80 recruitment to DNA lesions. TRAIP localizes to sites of DNA damage and cells lacking TRAIP exhibit classical DNA-damage response-defect phenotypes. Biochemical analysis reveals that the N terminus of TRAIP is crucial for RAP80 interaction, while the C terminus of TRAIP is required for TRAIP localization to sites of DNA damage through a direct interaction with RNF20–RNF40. Taken together, our findings demonstrate that the novel RAP80-binding partner TRAIP regulates recruitment of the damage signalling machinery and promotes homologous recombination.