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The DNA damage response (DDR) constitutes a vital cellular process that safeguards genome integrity. This biological process involves substantial alterations in chromatin structure, commonly orchestrated by epigenetic enzymes. Here, we show that the epigenetic modifier N-terminal acetyltransferase 4 (Nat4), known to acetylate the alpha-amino group of serine 1 on histones H4 and H2A, is implicated in the response to DNA damage in S. cerevisiae. Initially, we demonstrate that yeast cells lacking Nat4 have an increased sensitivity to DNA damage and accumulate more DNA breaks than wild-type cells. Accordingly, upon DNA damage, NAT4 gene expression is elevated, and the enzyme is specifically recruited at double-strand breaks. Delving deeper into its effects on the DNA damage signaling cascade, nat4-deleted cells exhibit lower levels of the damage-induced modification H2AS129ph (γH2A), accompanied by diminished binding of the checkpoint control protein Rad9 surrounding the double-strand break. Consistently, Mec1 kinase recruitment at double-strand breaks, critical for H2AS129ph deposition and Rad9 retention, is significantly impaired in nat4Δ cells. Consequently, Mec1-dependent phosphorylation of downstream effector kinase Rad53, indicative of DNA damage checkpoint activation, is reduced. Importantly, we found that the effects of Nat4 in regulating the checkpoint signaling cascade are mediated by its N-terminal acetyltransferase activity targeted specifically towards histone H4. Overall, this study points towards a novel functional link between histone N-terminal acetyltransferase Nat4 and the DDR, associating a new histone-modifying activity in the maintenance of genome integrity. Author summary: Chromatin structure alterations are central for cells to efficiently respond to DNA damage since DNA assaults do not simply occur on 'naked' DNA but in the context of chromatin. Cells have developed an integral process to mitigate DNA damage, known as the DNA damage response (DDR), which involves instrumental chromatin dynamic changes often regulated by histone-modifying enzymes. Our work demonstrates that N-terminal acetyltransferase Nat4 regulates the response to DNA damage. Importantly, cells lacking Nat4 are more susceptible to genotoxic-induced DNA damage, as well as accumulate higher number of DNA breaks. Accordingly, Nat4 expression is induced by DNA damage and specifically localizes at DNA double-strand breaks. In agreement with this, the absence of Nat4 impairs the DDR signaling, since the distribution of DNA damage-induced phosphorylation on serine 129 of histone H2A and the subsequent binding of Rad9 surrounding the break are robustly reduced. Both events are regulated by Mec1 kinase, whose recruitment at the DNA double-strand break is significantly decreased when Nat4 is absent. Consistently, downstream activation of the DNA damage checkpoint, indicative by Rad53 phosphorylation, is significantly reduced. Finally, this work supports that Nat4 functions in DNA damage response through its N-terminal acetyltransferase activity, specifically towards histone H4. Collectively, our data reveal a novel molecular and biological role for Nat4 in the response to DNA damage, and thus implicating a new player in genome integrity. [ABSTRACT FROM AUTHOR]

Context Over the past few decades, traditional foods have been displaced by ultra-processed foods (UPFs), with the latter being associated with health problems. Objective This scoping systematic review aimed to identify the relationship between UPF intake and overweight/obesity as well as other cardiometabolic risk factors during childhood and adolescence. Data Sources The guidance for this protocol is the Preferred Reporting Items for Systematic review and Meta-Analysis Protocols (PRISMA-P). A systematic search was undertaken on PubMed, Scopus, and Cochrane Library electronic databases based on prespecified inclusion and exclusion criteria up to 6 February 2022. Data Extraction A total of 17 observational studies—9 cross-sectional, 7 cohort-longitudinal, and 1 study reporting both cross-sectional and longitudinal outcomes—among children and adolescents aged ≤18 years were eligible for inclusion in this review. Fourteen studies evaluated the consumption of UPFs in association with overweight/obesity and 9 studies examined the association of UPF consumption and cardiometabolic-related risk factors. Data Analysis Most studies (14/17) showed that an increase in UPFs was associated with a higher prevalence of overweight/obesity and cardiometabolic comorbidities among children and adolescents, whereas 4 of 17 studies (3 cross-sectional and 1 cohort) found no association. Most cohort and cross-sectional studies showed good quality according to the National Institutes of Health and Newcastle-Ottawa quality assessment, respectively. Conclusion The positive association found between UPFs and overweight/obesity and cardiometabolic comorbidities among children and adolescents raises concerns for future health. Further investigation is recommended to explore the role of specific types of UPFs on cardiometabolic conditions and to identify the amount of daily intake that increase risk in order to shape appropriate public health policies. Systematic Review Registration PROSPERO registration no. CRD42022316432. [ABSTRACT FROM AUTHOR]