Inflammation is essential in protecting us against foreign pathogens. However when left unchecked, it becomes chronic inflammation, a potential precursor to carcinogenesis. While inflammatory signalling provides pro-survival stimuli, it also causes genomic instability and allows mutant cells to escape cell cycle arrest and apoptosis. This occurs through the release of reactive oxygen/nitrogen species (ROS/RNS), the increased expression of activation-induced cytidine deaminase (AID), inhibition of p53 function and the reactivation of TERT expression. Because chronic inflammation can ultimately lead to genomic instability, there is a need to target chronic inflammation, through the suppression of effector pathways with biologics or small molecules. More recently, therapies have also focused on stimulating physiological resolution, which offers a promising, tissue-specific alternative. As we better understand the triggers of chronic inflammation, therapies can be more specific, without compromising the overall functions of our immune system.

DNA double-strand breaks (DSBs) are cytotoxic lesions that will lead to genomic instability or even tumorigenesis if left unrepaired or misrepaired. To maintain homeostasis, cells have evolved two major repair pathways to counteract DSBs: classical non-homologous end joining (c-NHEJ) and homologous recombination (HR). Two other modes for repairing DSBs have been described: alternative non-homologous end joining (alt-NHEJ) and single-strand annealing (SSA). c-NHEJ ligates adjacent DSB ends directly with rapid kinetics throughout interphase, while HR meticulously initiates DNA-end resection in late S or G2 phase when sister chromatids are available as repair templates. Although partially sharing the DNA-end resection procedure with HR, alt-NHEJ and SSA often contribute to chromosomal translocation and genome rearrangement. Selection of the appropriate pathway to repair DSBs helps to maintain genome integrity. Here, we review current knowledge of the mechanisms regulating DSB repair pathway choice.

Ataxia-telangiectasia mutated (ATM) is an apical kinase involved in the cellular response to DNA damage in eukaryotes, especially DNA double-strand breaks (DSBs). Upon DSB, ATM is activated through a hierarchy of well-organized cellular processes and machineries, including post-translational modifications (PTMs), the MRE11-RAD50-NBS1 (MRN) complex and chromatin perturbations. ATM activation initiates a cascade of chromatin modifications and nucleosome remodeling that permits the assembly of repair factors that ensure a highly orchestrated response to repair damaged DNA. Numerous studies have tried to elucidate the mechanisms of ATM activation, but how it is activated by DNA damage signals is still unclear. Histone modifications are considered essential for regulating ATM activation: a histone octamer constitutes the nucleosome core and histone tails protrude into the DNA strands to alter the chromatin landscape and DNA accessibility. Here, we summarize how histone modifications regulate ATM activation, with an emphasis on the functional relevance in DNA damage response and repair.

Silent information regulator proteins (SIRT), or sirtuins, are evolutionarily conserved NAD⁺-dependent deacetylases and ADP-mono-ribosyltransferases. In mammalian, seven sirtuins have been identified, namely SIRT1–7, with different subcellular localization. Nuclear sirtuins, including SIRT1, SIRT6 and SIRT7, localize predominantly in the nucleus and are implicated in many vital biological processes, including stress response, transcription, genome maintenance, tumorigenesis and aging. Dysregulation of nuclear sirtuins is associated with the development of many diseases, including cancer and metabolic disorders. Therefore, the activities of nuclear sirtuins must be properly regulated. In this review, we summarize the current knowledge on the post-translational modifications of nuclear sirtuins and discuss how these modifications modulate their functions.