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,

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Evolution of erythrocyte transfusion-dependent (RBC-TD) anaemia associated with haploinsufficiency of the ribosomal protein subunit S14 gene (RPS14) is a characteristic complication of myelodysplastic syndromes (MDS) with del(5q) [MDS. del(5q)]. Evaluating 39 patients with MDS.del(5q), <5% of anaemia progression was attributable to RPS14-dependent alterations of normoblasts, pro-erythroblasts, or CD34 + CD71 + precursors. Ninety-three percent of anaemia progression and 70% of the absolute decline in peripheral blood Hb value were attributable to disappearance of erythroblastic islands (Ery-Is). Ery-Is loss occurred independently of blast excess, TP53 mutation, additional chromosome aberrations and RPS14-dependent alterations of normoblasts and pro-erythroblasts. It was associated with RPS14dependent intrinsic (S100A8 + ) and extrinsic [tumour necrosis factor α (TNF-α)overproduction] alterations of (CD169 + ) marrow macrophages (p < 0.00005). In a mouse model of RPS14 haploinsufficiency, Ery-Is disappeared to a similar degree: approximately 70% of Ery-Is loss was related to RPS14-dependent S100A8| 115 BUESCHE et al.