Τρίτη 27 Αυγούστου 2019

Crosstalk between signaling pathways and DNA damage response

Abstract

Living organisms have developed a complex signaling system to sense diverse growth signals and co-ordinate intracellular bioprocesses, so that they survive in various conditions. Since organisms are often exposed to environmental and genomic threats which cause DNA damages, DNA damage response (DDR) and repair systems are important for maintenance of genome stability and integrity. A line of evidences has demonstrated that there is tight crosstalk between growth signaling pathways and DDR systems. In this review, we give a brief overview of recent reports dissecting the interaction between signaling pathways and DDR at molecular level, which may further expand the knowledge of the signaling network and provide clues for disease therapy.

Regulation of DNA damage-induced ATM activation by histone modifications

Abstract

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.

ATM, DNA-PKcs and ATR: shaping development through the regulation of the DNA damage responses

Abstract

Genomic integrity is critical for normal development, healthy aging and suppressing oncogenic transformation. The DNA damage response (DDR) is a complex network that is activated by DNA structural changes to preserve genome integrity. Situated at the apex of the mammalian DDR are three PI3-kinase-related protein kinases—ATM, DNA-PKcs and ATR. They are activated by different DNA lesions via direct binding to their unique sensor protein complexes (MRE11-RAD50-NBS1 for ATM, Ku70-Ku80/86 for DNA-PKcs and ATRIP-RPA for ATR) and phosphorylate a large number of partially overlapping substrates, including themselves and each other to promote DNA repair and regulate cell cycle checkpoints and tissue homeostasis. This review focuses on mouse models with deletion and point mutations of ATM, DNA-PKcs and ATR, and discusses how their activation mechanism and their kinase activity contribute to their unique, yet interactive roles in DNA repair in general and during tissue-specific development processes and how their deficiency leads to specific physiological and pathophysiological consequences.

DNA double-strand break repair pathway choice: the fork in the road

Abstract

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.

Post-translational modifications of nuclear sirtuins

Abstract

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.

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