DNA-end resection is a highly regulated and critical step in the response and repair of DNA double-strand breaks. In higher eukaryotes, CtIP regulates resection by integrating cellular signals via its posttranslational modifications and protein-protein interactions, including cell-cycle-controlled interaction with BRCA1. The role of BRCA1 in DNA-end resection is not clear. Here, we develop an assay to study DNA resection in higher eukaryotes at high resolution. We demonstrate that the BRCA1-CtIP interaction, albeit not essential for resection, modulates the speed at which this process takes place.

There are two major and alternative pathways to repair DNA double-strand breaks: non-homologous end-joining and homologous recombination. Here we identify and characterize novel factors involved in choosing between these pathways; in this study we took advantage of the SeeSaw Reporter, in which the repair of double-strand breaks by homology-independent or -dependent mechanisms is distinguished by the accumulation of green or red fluorescence, respectively. Using a genome-wide human esiRNA (endoribonuclease-prepared siRNA) library, we isolate genes that control the recombination/end-joining ratio. Here we report that two distinct sets of genes are involved in the control of the balance between NHEJ and HR: those that are required to facilitate recombination and those that favour NHEJ. This last category includes CCAR2/DBC1, which we show inhibits recombination by limiting the initiation and the extent of DNA end resection, thereby acting as an antagonist of CtIP.

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Leptin is an important regulator of basal metabolism and food intake, with a pivotal role in obesity. Leptin exerts many different actions on various tissues and systems, including cancer, and is considered as a linkage between metabolism and the immune system. During the last decades, obesity and leptin have been associated with the initiation, proliferation and progression of many types of cancer. Obesity is also linked with complications and mortality, irrespective of the therapy used, affecting clinical outcomes. However, some evidence has suggested its beneficial role, called the “obesity paradox”, and the possible antitumoral role of leptin. Recent data regarding the immunotherapy of cancer have revealed that overweight leads to a more effective response and leptin may probably be involved in this beneficial process. Since leptin is a positive modulator of both the innate and the adaptive immune system, it may contribute to the increased immune response stimulated by immunotherapy in cancer patients and may be proposed as a good actor in cancer. Our purpose is to review this dual role of leptin in cancer, as well as trying to clarify the future perspectives of this adipokine, which further highlights its importance as a cornerstone of the immunometabolism in oncology.

While regulating the choice between homologous recombination and non-homologous end joining (NHEJ) as mechanisms of double-strand break (DSB) repair is exerted at several steps, the key step is DNA end resection, which in Saccharomyces cerevisiae is controlled by the MRX complex and the Sgs1 DNA helicase or the Sae2 and Exo1 nucleases. To assay the role of DNA resection in sister-chromatid recombination (SCR) as the major repair mechanism of spontaneous DSBs, we used a circular minichromosome system for the repair of replication-born DSBs by SCR in yeast. We provide evidence that MRX, particularly its Mre11 nuclease activity, and Sae2 are required for SCR-mediated repair of DSBs. The phenotype of nuclease-deficient MRX mutants is suppressed by ablation of Yku70 or overexpression of Exo1, suggesting a competition between NHEJ and resection factors for DNA ends arising during replication. In addition, we observe partially redundant roles for Sgs1 and Exo1 in SCR, with a more prominent role for Sgs1. Using human U2OS cells, we also show that the competitive nature of these reactions is likely evolutionarily conserved. These results further our understanding of the role of DNA resection in repair of replication-born DSBs revealing unanticipated differences between these events and repair of enzymatically induced DSBs.

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Background: Breast cancer is a major cause of cancer mortality worldwide. In Mexico, most cases are diagnosed in locally advanced stages, which is associated with a poor prognosis. Recent studies have suggested that 5-hydroxymethylcytosine (5hmC) levels could be a prognostic marker in cancer. However, the role of 5hmC as a predictor of histopathological alterations in breast cancer have not been fully studied. Results: We evaluated samples from patients with breast cancer (N=141), with a mean age of 50.12 yrs. (standard deviation [SD]: 9,54 yrs.), tumors showed a mean diameter of 6.53 cm (SD: 3.06 cm) at diagnosis, most of the patients showed overweight or obesity (77.3%) and most of them were locally advanced stage (n=111). A statistically significant and negative correlation between 5hmC levels and age in ER/PR-negative tumors (β =-0.028, 95% confidence interval [95%CI]:-0.045,-0.010, p-value = 0.005) and in triple negative tumors (β =-0.023, 95%CI:-0.044,-0.001, p-value = 0.046) was observed using mixed effects linear models. We also observed a negative correlation between 5hmC levels and an increased levels of cell proliferation markers, including Ki67 (r =-0.16, p-value < 0.01) and minichromosome maintenance complex component 2 [MCM2] (r =-0.21, p-value = 0.03). Finally, and using mixed effects models, we determined that the 5hmC level was an independent predictor of advanced histological grade in locally advanced breast cancer patients (β =-0.077, 95%CI-0.142,-0.011, p = 0.022). We did not observe differences associated with complete pathological response or free-relapse survival according to 5hmC level. Conclusions: This study suggests that low 5hmC may serve as potential marker of adverse histopathological characteristics in locally advanced breast cancer patients, highlighting its potential as a useful clinical biomarker.

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