"Nano-ghosts": Risk assessment of submicron-sized particles in food biased towards fictional "nano".

Much confusion has been generated in the safety assessment of food-grade TiO2 (E171) by the comingling of studies conducted on submicron-sized particles with those examining the toxicity of more minuscule counterparts. As E171 displays a nano-sized tail in its particle distribution (up to 36 % of particles with a diameter < 100 nm), it was thought that potential hazards of this food additive can be extrapolated from studies on thoroughly nanoscale formulations. This simplistic procedure may, however, overestimate the effects of the nano-sized tail of E171 because TiO2 particles readily aggregate or agglomerate in aqueous suspensions and biological matrices. The resulting larger clusters display a reduced oral bioavailability in comparison to the same material in nano-sized dimensions. Also, even if taken up in trace amounts, the smaller particles likely remain appended to larger particles or clusters and these aggregates or conglomerates may nullify to a great extent their "nano" characteristics. The purpose of this review is, therefore, to reevaluate the literature on the toxicity of TiO2 particles focusing on studies that are directly relevant for the assessment of E171. The purpose is not to avert a ban on the use of E171 in food, which might well be justified in light of the uncertainties associated with this additive employed solely for its colorant properties. Instead, it will be important to avoid in the future this same bias towards a fictional "nano" hazard, especially when evaluating more innovative engineered particles that confer true benefits for example by enhancing nutritional properties, quality, freshness, traceability or sustainability of food.

Persistent DNA damage triggers activation of the integrated stress response to promote cell survival under nutrient restriction.

BACKGROUND: Base-excision repair (BER) is a central DNA repair mechanism responsible for the maintenance of genome integrity. Accordingly, BER defects have been implicated in cancer, presumably by precipitating cellular transformation through an increase in the occurrence of mutations. Hence, tight adaptation of BER capacity is essential for DNA stability. However, counterintuitive to this, prolonged exposure of cells to pro-inflammatory molecules or DNA-damaging agents causes a BER deficiency by downregulating the central scaffold protein XRCC1. The rationale for this XRCC1 downregulation in response to persistent DNA damage remains enigmatic. Based on our previous findings that XRCC1 downregulation causes wide-ranging anabolic changes, we hypothesised that BER depletion could enhance cellular survival under stress, such as nutrient restriction. RESULTS: Here, we demonstrate that persistent single-strand breaks (SSBs) caused by XRCC1 downregulation trigger the integrated stress response (ISR) to promote cellular survival under nutrient-restricted conditions. ISR activation depends on DNA damage signalling via ATM, which triggers PERK-mediated eIF2α phosphorylation, increasing translation of the stress-response factor ATF4. Furthermore, we demonstrate that SSBs, induced either through depletion of the transcription factor Sp1, responsible for XRCC1 levels, or through prolonged oxidative stress, trigger ISR-mediated cell survival under nutrient restriction as well. Finally, the ISR pathway can also be initiated by persistent DNA double-strand breaks. CONCLUSIONS: Our results uncover a previously unappreciated connection between persistent DNA damage, caused by a decrease in BER capacity or direct induction of DNA damage, and the ISR pathway that supports cell survival in response to genotoxic stress with implications for tumour biology and beyond.

A chromatin scaffold for DNA damage recognition: how histone methyltransferases prime nucleosomes for repair of ultraviolet light-induced lesions.

The excision of mutagenic DNA adducts by the nucleotide excision repair (NER) pathway is essential for genome stability, which is key to avoiding genetic diseases, premature aging, cancer and neurologic disorders. Due to the need to process an extraordinarily high damage density embedded in the nucleosome landscape of chromatin, NER activity provides a unique functional caliper to understand how histone modifiers modulate DNA damage responses. At least three distinct lysine methyltransferases (KMTs) targeting histones have been shown to facilitate the detection of ultraviolet (UV) light-induced DNA lesions in the difficult to access DNA wrapped around histones in nucleosomes. By methylating core histones, these KMTs generate docking sites for DNA damage recognition factors before the chromatin structure is ultimately relaxed and the offending lesions are effectively excised. In view of their function in priming nucleosomes for DNA repair, mutations of genes coding for these KMTs are expected to cause the accumulation of DNA damage promoting cancer and other chronic diseases. Research on the question of how KMTs modulate DNA repair might pave the way to the development of pharmacologic agents for novel therapeutic strategies.