Systemic DNA damage responses in aging and diseases

Abstract

The genome is constantly attacked by a variety of genotoxic insults. The causal role for DNA damage in aging and cancer is exemplified by genetic defects in DNA repair that underlie a broad spectrum of acute and chronic human disorders that are characterized by developmental abnormalities, premature aging, and cancer predisposition. The disease symptoms are typically tissue-specific with uncertain genotype-phenotype correlation. The cellular DNA damage response (DDR) has been extensively investigated ever since yeast geneticists discovered DNA damage checkpoint mechanisms, several decades ago. In recent years, it has become apparent that not only cell-autonomous but also systemic DNA damage responses determine the outcome of genome instability in organisms. Understanding the mechanisms of non-cell-autonomous DNA damage responses will provide important new insights into the role of genome instability in human aging and a host of diseases including cancer and might better explain the complex phenotypes caused by genome instability. The cellular DNA damage response (DDR)The genetic information is constantly threatened by a plethora of genotoxic attacks. DNA damage can be caused by a variety of exogenous or endogenous agents. The first are environmental agents such as ultraviolet (UV) light, ionizing radiation (IR), as well as many genotoxic chemicals. The latter are by-products of cellular metabolic circuits such as oxidative respiration or events such as lipid peroxidation, which give rise to reactive oxidative species (ROS). In addition, spontaneous events constantly challenge the stability of DNA chemical bonds [1]. Depending on the source of damage, DNA can be affected in different ways, varying from single-strand breaks (SSBs), abasic sites and modified bases to highly toxic lesions such as small or bulky adducts and lesions, interstrand crosslinks (ICLs) and double-strand breaks (DSBs) (Figure 1). Lesions might compromise DNA metabolism by interrupting replication or transcription. It is thought that DNA damage accumulation with aging results in loss of cellular functionality and ultimately degeneration of cells and tissues. Erroneous repair, however, can lead to mutations and chromosomal aberrations,

DNA Damage Response and Autophagy: A Meaningful Partnership

“…If unrepaired, DNA lesions may result in cell death (Roos et al, 2016) but can also be a major source of genomic instability particularly when cell death pathways have been deactivated (Halazonetis et al, 2008). DDR signaling has been extensively reviewed elsewhere (Halazonetis et al, 2008; Jackson and Bartek, 2009; Marechal and Zou, 2013; Ribezzo et al, 2016); below we provide a summary of some of its components and their functions which are most relevant to this review.…”

“…Depending on the type of damage and the phase of the cell cycle, different repair mechanisms are utilized to restore DNA integrity (Jackson and Bartek, 2009; Ribezzo et al, 2016). For example, PARP1 is involved in the repair of single strand DNA breaks by recruiting enzymes necessary for base excision repair such as XRCC1, polymerase β and DNA ligase III to the sites of damage (de Murcia et al, 1997).…”

“…Whereas these studies have not addressed the impact of autophagy on IL-1β biogenesis and secretion in response to genotoxic stress, it is likely that autophagy has a broader role in influencing the extent and duration of inflammation. This may be of particular relevance to and warrants further investigations in aging which is typified in humans by chronic, low-level inflammation, termed ‘inflammaging’ (Franceschi and Campisi, 2014), accumulated genomic damage (Ribezzo et al, 2016) and reduced autophagic activity (Martinez-Lopez et al, 2015). …”

A C. elegans homolog for the UV-hypersensitivity syndrome disease gene UVSSA

“…C. elegans is being increasingly used for the characterization of various DNA repair pathways since most of the major mammalian repair pathways, including NER, are conserved at the molecular level in this organism [17,18]. C. elegans has a functional NER that repairs UV-induced DNA damage [19,20] with the CSB homolog csb-1 and XPC homolog xpc-1 igniting TC-NER and GG-NER, respectively.…”

Systemic dna damage: Mechanisms, effects and mitigation strategies

“…Therefore they conclude that understanding the mechanisms of non-cell-autonomous DNA damage responses will provide important new insights into the role of genome instability in human aging and a host of diseases including cancer. This consequently might help towards better explaining of the complex phenotypes instigated by genome instability [6]. Passing from aging to cancer (4) Orsolic et al focus on the role of dysregulation of some fundamental cellular processes that may contribute to the malignant phenotype and underline the importance of normal functioning of the nucleolus that safeguards against the development of cancer.…”