In response to DNA damage, cells activate a complex, kinase-based signaling network to arrest the cell cycle and allow time for DNA repair, or, if the extend of damage is beyond repair capacity, induce apoptosis. This signaling network, which is collectively referred to as the DNA damage response (DDR), is primarily thought to consist of two components—a rapid phosphorylation-driven signaling cascade that results in immediate inhibition of Cdk/cyclin complexes and a delayed transcriptional response that promotes a prolonged cell cycle arrest through the induction of Cdk inhibitors, such as p21. In recent years a third layer of complexity has emerged that involves potent posttranscriptional regulatory mechanisms that control the cellular response to DNA damage. Although much has been written on the relevance of the DDR in cancer and on the post-transcriptional role of microRNAs (miRs) in cancer, the post-transcriptional regulation of the DDR by non-coding RNAs and RNA-binding proteins (RBPs) still remains elusive in large parts. Here, we review the recent developments in this exciting new area of research in the cellular response to genotoxic stress. We put specific emphasis on the role of RBPs and the control of their function through DNA damage-activated protein kinases.

Following genotoxic stress, cells activate a complex, kinase-based signaling network to arrest the cell cycle and initiate DNA repair or apoptosis. The tumor suppressor p53 lies at the heart of this DNA damage response. p53 mediates the transactivation of both cell cycle-regulating and pro-apoptotic clusters of target genes. However, it remains incompletely understood which signaling molecules dictate the choice between these two opposing p53-dependent cellular outcomes. Over recent years, numerous regulatory mechanisms impacting on the cellular outcome of p53 signaling have been described. However, no single dominant mechanism has thus far been identified to regulate the cellular choice between p53-driven apoptosis or senescence. The transcriptional regulator AATF has recently emerged as a novel factor impacting on the cellular outcome of the p53 response. Upon genotoxic stress, cytoplasmic pools of MRLC-bound AATF are phosphorylated through the p38MAPK/MK2 checkpoint kinase complex. This AATF phosphorylation results in the disruption of cytoplasmic MRLC3:AATF complexes followed by rapid nuclear localization of AATF. Once in the nucleus, AATF binds to the PUMA, BAX and BAK promoters to repress the DNA damage-induced expression of these pro-apoptotic p53 target genes. Depletion of AATF in tumor cells results in a dramatically enhanced response to DNA-damaging chemotherapeutics, both in vitro and in vivo. Furthermore, focal copy number gains at the AATF locus in neuroblastoma correlate with adverse prognosis and reduced overall survival in this typically p53-proficient malignancy. These data identify the p38/MK2/AATF signaling pathway as a critical repressor of p53-driven apoptosis in tumor cells and implicate this signaling cascade as a novel target for chemotherapy-sensitizing therapeutic efforts.

Multiple myeloma (MM) is a hematologic malignancy produced by a clonal expansion of plasma cells and characterized by abnormal production and secretion of monoclonal antibodies. This pathology exhibits an enormous heterogeneity resulting not only from genetic alterations but also from several epigenetic dysregulations. Here we provide evidence that Che-1/AATF (Che-1), an interactor of RNA polymerase II, promotes MM proliferation by affecting chromatin structure and sustaining global gene expression. We found that Che-1 depletion leads to a reduction of “active chromatin” by inducing a global decrease of histone acetylation. In this context, Che-1 directly interacts with histones and displaces histone deacetylase class I members from them. Strikingly, transgenic mice expressing human Che-1 in plasma cells develop MM with clinical features resembling those observed in the human disease. Finally, Che-1 downregulation decreases BRD4 chromatin accumulation to further sensitize MM cells to bromodomain and external domain inhibitors. These findings identify Che-1 as a promising target for MM therapy, alone or in combination with bromodomain and external domain inhibitors.

Chronic Kidney Disease (CKD), a global health burden, is strongly associated with age-related renal function decline, hypertension, and diabetes, which are all frequent consequences of obesity. Despite extensive studies, the mechanisms determining susceptibility to CKD remain insufficiently understood. Clinical evidence together with prior studies from our group showed that perinatal metabolic disorders after intrauterine growth restriction or maternal obesity adversely affect kidney structure and function throughout life. Since obesity and aging processes converge in similar pathways we tested if perinatal obesity caused by high-fat diet (HFD)-fed dams sensitizes aging-associated mechanisms in kidneys of newborn mice. The results showed a marked increase of γH2AX-positive cells with elevated 8-Oxo-dG (RNA/DNA damage), both indicative of DNA damage response and oxidative stress. Using unbiased comprehensive transcriptomics we identified compartment-specific differentially-regulated signaling pathways in kidneys after perinatal obesity. Comparison of these data to transcriptomic data of naturally aged kidneys and prematurely aged kidneys of genetic modified mice with a hypomorphic allele of Ercc1, revealed similar signatures, e.g., inflammatory signaling. In a biochemical approach we validated pathways of inflammaging in the kidneys after perinatal obesity. Collectively, our initial findings demonstrate premature aging-associated processes as a consequence of perinatal obesity that could determine the susceptibility for CKD early in life.

Objectives: About 90% of all non-small cell lung cancer (NSCLC) cases are associated with inhalative tabacco smoking. Half of patients continue smoking during lung cancer therapy. We examined the effects of postoperative smoking cessation on lung function, quality of life (QOL) and long-term survival. Materials and Methods: In total, 641 patients, who underwent lobectomy between 2012 and 2019, were identified from our single institutional data base. Postoperatively, patients that actively smoked at the time of operation were offered a structured ‘smoking cessation’ program. For this retrospective analysis, two patient groups (total n = 90) were selected by pair matching. Group A (n = 60) had no postoperative tobacco smoking. Group B (n = 30) involved postoperative continued smoking. Lung function (FEV1, DLCO) and QOL (‘SF-36′ questionnaire) were measured 12 months postoperatively. We compared long-term outcomes using Kaplan–Meier curves. Results: The mean age in group A was 62.6 ± 12.5 years and that in group B was 64.3 ± 9.7 years (p = 0.82); 64% and 62%, respectively, were male (p = 0.46). Preoperative smoking habits were similar (‘pack years’: group A, 47 ± 31; group B, 49 ± 27; p = 0.87). All relevant baseline characteristics we collected were similar (p > 0.05). One year after lobectomy, FEV1 was reduced by 15% in both groups (p = 0.98). Smoking cessation was significantly associated with improved DLCO (group A: 11 ± 16%; group B: −5 ± 14%; p <0.001) and QOL (vitality (VT): +10 vs. −10, p = 0.017; physical role function (RP): +8 vs. −17, p = 0.012; general health perceptions (GH): +12 vs. −5, p = 0.024). Patients who stopped smoking postoperatively had a significantly superior overall survival (median survival: 89.8 ± 6.8 [95% CI: 76.6–103.1] months vs. 73.9 ± 3.6 [95% CI: 66.9–80.9] months, p = 0.034; 3-year OS rate: 96.2% vs. 81.0%, p = 0.02; 5-year OS rate: 80.0% vs. 64.0%, p = 0.016). The hazard ratio (HR) was 2.31 [95% CI: 1.04–5.13] for postoperative smoking versus tobacco cessation. Conclusion: Postoperative smoking cessation is associated with improved quality of life and lung function testing. Notably, a significant increase in long-term survival rates among non-smoking NSCLC patients was observed. These findings could serve as motivation for patients to successfully complete a non-smoking program.

Objectives: Classifying radiologic pulmonary lesions as malignant is challenging. Scoring systems like the Mayo model lack precision in predicting the probability of malignancy. We developed the logistic scoring system ‘LIONS PREY’ (Lung lesION Score PREdicts malignancY), which is superior to existing models in its precision in determining the likelihood of malignancy. Methods: We evaluated all patients that were presented to our multidisciplinary team between January 2013 and December 2020. Availability of pathological results after resection or CT-/EBUS-guided sampling was mandatory for study inclusion. Two groups were formed: Group A (malignant nodule; n = 238) and Group B (benign nodule; n = 148). Initially, 22 potential score parameters were derived from the patients’ medical histories. Results: After uni- and multivariate analysis, we identified the following eight parameters that were integrated into a scoring system: (1) age (Group A: 64.5 ± 10.2 years vs. Group B: 61.6 ± 13.8 years; multivariate p-value: 0.054); (2) nodule size (21.8 ± 7.5 mm vs. 18.3 ± 7.9 mm; p = 0.051); (3) spiculation (73.1% vs. 41.9%; p = 0.024); (4) solidity (84.9% vs. 62.8%; p = 0.004); (5) size dynamics (6.4 ± 7.7 mm/3 months vs. 0.2 ± 0.9 mm/3 months; p < 0.0001); (6) smoking history (92.0% vs. 43.9%; p < 0.0001); (7) pack years (35.1 ± 19.1 vs. 21.3 ± 18.8; p = 0.079); and (8) cancer history (34.9% vs. 24.3%; p = 0.052). Our model demonstrated superior precision to that of the Mayo score (p = 0.013) with an overall correct classification of 96.0%, a calibration (observed/expected-ratio) of 1.1, and a discrimination (ROC analysis) of AUC (95% CI) 0.94 (0.92–0.97). Conclusions: Focusing on essential parameters, LIONS PREY can be easily and reproducibly applied based on computed tomography (CT) scans. Multidisciplinary team members could use it to facilitate decision making. Patients may find it easier to consent to surgery knowing the likelihood of pulmonary malignancy. The LIONS PREY app is available for free on Android and iOS devices.