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Context.— Special AT-rich sequence–binding protein 2 (SATB2) induces local chromatin loops to facilitate transcription. SATB2 immunostaining is commonly used as a marker for colorectal adenocarcinoma and osteosarcoma. Objective.— To extend our knowledge on the diagnostic value of SATB2 analysis in a comprehensive set of human tumors. Design.— Tissue microarrays with 15 012 samples from 120 tumor types and 608 samples of 76 different normal tissues were analyzed. Results.— SATB2 positivity was found in 89 of 120 different tumor types (74%), including 59 of 120 (49%) with at least 1 moderately positive tumor and 38 of 120 tumor types (32%) with at least 1 strongly positive tumor. Expression was frequent in adenomas (44/42–47/44; 94%–96% positive), adenocarcinomas (1747 of 2023; 86%), and various subtypes of neuroendocrine neoplasms (3/7–12/12; 43%–100%) of the colorectum and appendix, Merkel cell carcinoma (25 of 34, 74%), osteosarcomas (15 of 25; 60%), and papillary renal cell carcinoma (RCC) (121 of 235; 52%). Associations to clinicopathologic tumor features were assessed in colorectal and kidney cancers. In colorectal cancer, weak SATB2 expression was linked to high pT (P < .001), nodal metastasis (P < .001), right-sided tumor location (P < .001), microsatellite instability (P < .001), and BRAF mutations (P = .02). In papillary RCC, low SATB2 expression was associated with high pT (P = .02), distant metastasis (P = .04), and reduced tumor-specific survival (P = .04). In clear cell RCC, low SATB2 expression was linked to high pT (P < .001), high Union for International Cancer Control stage (P < .001), high Thoenes grade (P = .02), and reduced recurrence-free survival (P = .02). Conclusions.— Strong SATB2 expression argues for a colorectal origin within adenocarcinomas and neuroendocrine neoplasms. Weak SATB2 expression reflects progression and poor prognosis in colorectal and kidney cancer.

The Sixth Assessment Report from the Intergovernmental Panel on Climate Change emphasized on the water cycle, and water-related disasters (i.e., water scarcity, droughts, floods) that impact all sectors and regions. Therefore, assessing future water availability is critical to develop mitigation strategies and formulate adaptation policies. While developing relevant information systems, it is critical to ensure the involvement of stakeholders in the field of policy development, communities impacted by future water availability (e.g., agriculture, fisheries, shipping industry), and private industries (e.g., paper and pulp, hydropower) to ensure that information presented can be useful to support decision making. Destination Earth (DestinE) aims to, among other products, to develop – on a global scale – a highly accurate digital model of the Earth to monitor and predict the interaction between natural phenomena and human activities. As part of the European Commission’s Green Deal and Digital Strategy, DestinE will contribute to achieving the objectives of the twin transition, green and digital. High resolution climate simulations (ICON and IFS climate models) are used as meteorological forcings for the mesoscale Hydrological Model (mHM) to produce high temporal (1 hour) and spatial resolution (5 km) streamflow estimates at a global scale. The impact model consists of the mHM model, which includes key hydrological processes e.g., run-off, soil moisture dynamics, fast and slow interflow processes to estimate river discharge. The application prototype will provide: 1) co-designing the indicators and indices as well as application functionalities together with relevant stakeholders. 2) downscaling of the essential climate variables 3) providing bias correction for the climate variables 4) running the mHM model under various climate scenarios. In addition, the application will receive data through direct streaming from the climate simulations thus ensuring interactivity of the application for the users. During the development phase of the DestinE digital twin, the climate simulations used in the current work are taken from the results of the NextGEMS project. They have been used to provide a proof of concept for the mHM model, and provide initial results for stakeholder engagement, and enable early involvement of stakeholders in the co-design of relevant applications.

Germany experienced exceptional multi-year water storage deficits starting in 2018. Recurring years below average precipitation and above average temperatures lead to water deficits that accumulated primarily in slow-response subsurface water storages such as (deep) soil moisture or groundwater levels. Total water storage (TWS) anomalies estimated by the GRACE satellite mission show a strong decline for Germany since measurements began in 2002, but these time series began with a relatively wet period, ended in an exceptional drought situation, and are still relatively short. Therefore the resulting trends are not representative for long-term TWS dynamics and should not be used to extrapolate the development into the future (Güntner et al, 2022). In addition, the GRACE signal does not allow partitioning of the water storage and flux components. Hydrological simulations provide a suitable tool to analyse the long-term dynamics of water storages. We analyse the long-term monthly TWS anomalies estimated with the hydrological model mHM (Samaniego et al. (2010), Kumar et al. (2013)) from a data reconstruction starting in 1766 (Rakovec et al, 2022). Comparison of the monthly total water storage estimates between the hydrological simulations and two GRACE solutions (JPL RL06M MSCNv02CRI, GFZ COST-G RL01) show good agreement for both anomalies (R²=0.78-0.84) and the residuals after removing the seasonal cycle (R²=0.69-0.72) on the scale of Germany (spatial mean). We specifically examine the periods of recovery from total water storage deficits from a water balance perspective. Besides precipitation (P) being the main driver of changes in the TWS, the progress of recovery from water storage deficits is controlled by the main water fluxes evapotranspiration (E) and runoff (Q) that are the loss terms in the water balance equation deltaTWS = P - E - Q. Decadal evaluations indicate that the water balance in Germany in recent decades has been increasingly driven by above-average E as a result of the temperature rise. While the cumulative precipitation deficits in the last decade 2011 - 2020 are less exceptional compared to other historical decades, cumulative E residuals account for a much larger part of the water deficits than in other historical decades. The results will contribute to an improved understanding how TWS deficit recovery are affected by long-term changes in the water balance. References: Güntner, A., Gerdener, H., Boergens, E., Kusche, J., Kollet, S., Dobslaw, H., Hartick, C., Sharifi, E., and Flechtner, F. (2022): Changes of water storage in Germany since 2002 observed with GRACE/GRACE-FO, GRACE/GRACE-FO Science Team Meeting 2022, Potsdam, Germany, 18–20 Oct 2022, GSTM2022-93, https://doi.org/10.5194/gstm2022-93. Rakovec, O., Samaniego, L., Hari, V., Markonis, Y., Moravec, V., Thober, S., Hanel, M., & Kumar, R. (2022): The 2018–2020 Multi‐Year Drought Sets a New Benchmark in Europe. In Earth’s Future (Vol. 10, Issue 3). American Geophysical Union (AGU). https://doi.org/10.1029/2021ef002394 Samaniego L., R. Kumar, S. Attinger (2010): Multiscale parameter regionalization of a grid-based hydrologic model at the mesoscale. Water Resour. Res., 46,W05523, doi:10.1029/2008WR007327 Kumar, R., L. Samaniego, and S. Attinger (2013): Implications of distributed hydrologic model parameterization on water fluxes at multiple scales and locations, Water Resour. Res., 49, doi:10.1029/2012WR012195

The tumor suppressor protein fragile histidine triad (Fhit) is known to be associated with genomic instability and apoptosis. The tumor-suppressive function of Fhit depends on the interaction with the alarmone diadenosine triphosphate (Ap3A), a noncanonical nucleotide whose concentration increases upon cellular stress. How the Fhit–Ap3A complex exerts its signaling function is unknown. Here, guided by a chemical proteomics approach employing a synthetic stable Fhit–Ap3A complex, we found that the Fhit–Ap3A complex, but not Fhit or Ap3A alone, impedes translation. Our findings provide a mechanistic model in which Fhit translocates from the nucleolus into the cytosol upon stress to form an Fhit–Ap3A complex. The Fhit–Ap3A complex impedes translation both in vitro and in vivo, resulting in reduced cell viability. Overall, our findings provide a mechanistic model by which the tumor suppressor Fhit collaborates with the alarmone Ap3A to regulate cellular proliferation. published

More than 170 posttranscriptional RNA modifications are so far known on both coding and noncoding RNA species. Within this group, pseudouridine (Ψ) and queuosine (Q) represent conserved RNA modifications with fundamental functional roles in regulating translation. Current detection methods of these modifications, which both are reverse transcription (RT)-silent, are mostly based on the chemical treatment of RNA prior to analysis. To overcome the drawbacks associated with indirect detection strategies, we have engineered an RT-active DNA polymerase variant called RT-KTq I614Y that produces error RT signatures specific for Ψ or Q without prior chemical treatment of the RNA samples. Combining this polymerase with next-generation sequencing techniques allows the direct identification of Ψ and Q sites of untreated RNA samples using a single enzymatic tool.

Agricultural production is highly dependent on the weather. The mechanisms of action are complex and interwoven, making it difficult to identify relevant management and adaptation options. The present study uses random forests to investigate such highly non-linear systems for predicting yield anomalies in winter wheat at district levels in Germany. In order to take into account sub-seasonality, monthly features are used that explicitly take soil moisture into account in addition to extreme meteorological events. Clustering is used to show spatially different damage potentials, such as a higher susceptibility to drought damage from May to July in eastern Germany compared to the rest of the country. In addition, relevant heat effects are not detected if the clusters are not sufficiently defined. The variable with the highest importance is soil moisture in March, where higher soil moisture has a detrimental effect on crop yields. In general, soil moisture explains more yield variations than the meteorological variables. The approach has proven to be suitable for explaining historical extreme yield anomalies for years with exceptionally high losses (2003, 2018) and gains (2014) and the spatial distribution of these anomalies. The highest test R-squared (R2) is about 0.68. Furthermore, the sensitivity of yield variations to soil moisture and extreme meteorological conditions, as shown by the visualization of average marginal effects, contributes to the promotion of targeted decision support systems.

The development of an improved kilogram-scale synthesis of the JAK1 inhibitor GDC-4379 for the treatment of asthma is described. The new process is highlighted by a step-economical construction of ...

Diadenosine polyphosphates (ApnAs) are non-canonical nucleotides whose cellular concentrations increase during stress and are therefore termed alarmones, signaling homeostatic imbalance. Their cellular role is poorly understood. In this work, we assessed ApnAs for their usage as cosubstrate for protein AMPylation, a post-translational modification in which adenosine monophosphate (AMP) is transferred to proteins. In humans, AMPylation mediated by the AMPylator FICD with ATP as cosubstrate is a response to ER stress. Here, we demonstrate that Ap4A is proficiently consumed for AMPylation by FICD. By chemical proteomics using a new chemical probe, we identified new potential AMPylation targets. Interestingly, we found that AMPylation targets of FICD may differ depending on the nucleotide cosubstrate. These results may suggest that signaling at elevated Ap4A levels during cellular stress differs from when Ap4A is present at low concentrations allowing response to extracellular cues. published

Diadenosinpolyphosphate (ApnAs) sind nicht-kanonische Nukleotide, deren zelluläre Konzentrationen bei Stress als Signal eines homöostatischen Ungleichgewichts ansteigen und die daher als Alarmone bezeichnet werden. Ihre zelluläre Rolle ist nur unzureichend verstanden. In dieser Arbeit haben wir untersucht, ob ApnAs als Cosubstrat für die AMPylierung von Proteinen verwendet werden. AMPylierung ist eine posttranslationale Modifikation, bei der Adenosinmonophosphat (AMP) auf Proteine übertragen wird. Beim Menschen ist die AMPylierung, die durch den AMPylator FICD mit ATP als Cosubstrat vermittelt wird, eine Reaktion auf ER-Stress. Hier zeigen wir, dass Ap4A für die AMPylierung durch FICD effizient verwendet wird. Durch chemische Proteomik unter Verwendung einer neuen chemischen Sonde haben wir neue potenzielle AMPylierungsziele identifiziert. Interessanterweise haben wir festgestellt, dass sich die AMPylierungsziele von FICD je nach Nukleotid-Cosubstrat unterscheiden können. Diese Ergebnisse könnten darauf hindeuten, dass sich die Signalübertragung bei erhöhten Ap4A-Spiegeln während zellulärem Stress von derjenigen bei niedrigen Ap4A Konzentrationen unterscheidet, und damit eine Reaktion auf extrazelluläre Signale ermöglicht. published

Late-stage functionalization (LSF) is an economical approach to optimize the properties of drug candidates. However, the chemical complexity of drug molecules often makes late-stage diversification challenging. To address this problem, an LSF platform based on geometric deep learning and high-throughput reaction screening was developed. Considering borylation as a critical step in LSF, the computational model predicted reaction yields for diverse reaction conditions with a mean absolute error margin of 4–5%, while the reactivity of novel reactions with known and unknown substrates were classified with a balanced accuracy of 92% and 67%, respectively. The regioselectivity of the major products was accurately captured in up to 90% of the cases studied. When applied to 23 diverse commercial drug molecules, the platform successfully identified numerous opportunities for structural diversification. The influence of steric and quantum mechanical information on model performance was quantified and a new comprehensive simple user-friendly reaction format (SURF) is introduced which proved to be a key enabler for seamlessly integrating deep learning and high-throughput experimentation (HTE) for LSF.

Reverse transcriptases are DNA polymerases that can use RNA as a template for DNA synthesis. They thus catalyze the reverse of transcription. Although discovered in 1970, reverse transcriptases are still of great interest and are constantly being further developed for numerous modern research approaches. They are frequently used in biotechnological and molecular diagnostic applications. In this review, we describe the discovery of these fascinating enzymes and summarize research results and applications ranging from molecular cloning, direct virus detection, and modern sequencing methods to xenobiology. published

Carboxypeptidase A1 (CPA1) is a zinc metalloprotease that is produced in pancreatic acinar cells and plays a role in cleaving C-terminal branched-chain and aromatic amino acids from dietary proteins. This study assessed the utility of immunohistochemical CPA1 staining for diagnosing pancreatic acinar cell carcinoma (ACC). A total of 12,274 tumor samples from 132 different tumor types and subtypes as well as 8 samples each of 76 different normal tissue types were interpretable by immunohistochemistry in a tissue microarray format. CPA1 was strongly expressed in acinar cells of all normal pancreas samples but not in any other normal tissues. CPA1 immunostaining was detected in 100% of 11 pancreatic ACCs and 1 mixed acinar endocrine carcinoma, but absent in 449 pancreatic ductal adenocarcinomas, 75 adenocarcinomas of the ampulla Vateri, and 11,739 other evaluable cancers from 128 different tumor entities. A weak to moderate diffuse staining of epithelial and stromal cells of cancer tissues immediately adjacent to non-neoplastic pancreatic acinar cells often occurred and was considered to be caused by the diffusion of the highly abundant CPA1 from normal acinar cells that may have suffered some autolytic cell damage. In conclusion, our data show that CPA1 is a highly sensitive and largely specific marker for normal and neoplastic pancreatic acinar cells. CPA1 immunohistochemistry greatly facilitates the otherwise often difficult diagnosis of pancreatic ACC.

To evaluate cytokeratin 19 (CK19) expression in normal and cancerous tissues, 15,977 samples from 122 tumor types and 608 samples of 76 normal tissue types were analyzed by immunohistochemistry (IHC). In normal tissues, CK19 expression occurred in epithelial cells of most glandular organs but was strictly limited to the basal cell layer of nonkeratinizing squamous epithelium and absent in the skin. CK19 expression in ≥90% of cases was seen in 34% of the tumor entities including the adenocarcinomas of the pancreas (99.4%), colorectum (99.8%), esophagus (98.7%), and stomach (97.7%), as well as breast cancer (90.0%-100%), high-grade serous (99.1%) or endometrioid (97.8%) ovarian cancer, and urothelial carcinoma (92.6%-100%). A low CK19 positivity rate (0.1-10%) was seen in 5 of 122 tumor entities including hepatocellular carcinoma and seminoma. A comparison of tumor versus normal tissue findings demonstrated that upregulation and downregulation of CK19 can occur in cancer and that both alterations can be linked to unfavorable phenotypes. CK19 downregulation was linked to high grade (p = 0.0017) and loss of estrogen receptor- and progesterone receptor-expression (p 0.0001 each) in invasive breast carcinoma of no special type. CK19 upregulation was linked to nodal metastases in neuroendocrine tumors and papillary thyroid carcinomas (p 0.05 each) and to poor grade in clear cell renal cell carcinoma (p 0.05). CK19 upregulation was particularly common in squamous cell carcinomas. We concluded that CK19 IHC might separate primary liver cell carcinoma from liver metastases, seminoma from other testicular tumors, and helps in the detection of early neoplastic transformation in squamous epithelium.

Linker histone H1 plays a key role in chromatin organization and maintenance, yet our knowledge of the regulation of H1 functions by post-translational modifications is rather limited. In this study, we report on the generation of site-specifically mono- and di-acetylated linker histone H1.2 by genetic code expansion. We used these modified histones to identify and characterize the acetylation-dependent cellular interactome of H1.2 by affinity purification mass spectrometry and show that site-specific acetylation results in overlapping but distinct groups of interacting partners. Among these, we find multiple translational initiation factors and transcriptional regulators such as the NAD+-dependent deacetylase SIRT1, which we demonstrate to act on acetylated H1.2. Taken together, our data suggest that site-specific acetylation of H1.2 plays a role in modulating protein-protein interactions.

Intracellular dinucleoside polyphosphates (Npn Ns) have been known for decades but the functional role remains enigmatic. Diadenosine triphosphate (Ap3 A) is one of the most prominent examples, and its intercellular concentration was shown to increase upon cellular stress. By employment of previously reported Ap3 A-based photoaffinity-labeling probes (PALPs) in chemical proteomics, we investigated the Ap3 A interactome in the human lung carcinoma cell line H1299. The cell line is deficient of the fragile histidine triade (Fhit) protein, a hydrolase of Ap3 A and tumor suppressor. Overall, the number of identified potential interaction partners was significantly lower than in the previously investigated HEK293T cell line. Gene ontology term analysis revealed that the identified proteins participate in similar pathways as for HEK293T, but the percentage of proteins involved in RNA-related processes is higher for H1299. The obtained results highlight similarities and differences of the Ap3 A interaction network in different cell lines and give further indications regarding the importance of the presence of Fhit. published

The chromatin in eukaryotic cells plays a fundamental role in all processes during a cell’s life cycle. This nucleoprotein is normally tightly packed but needs to be unpacked for expression and division. The linker histones are critical for such packaging processes and while most experimental and simulation works recognize their crucial importance, the focus is nearly always set on the nucleosome as the basic chromatin building block. Linker histones can undergo several modifications, but only few studies on their ubiquitylation have been conducted. Mono-ubiquitylated linker histones (HUb), while poorly understood, are expected to influence DNA compaction. The size of ubiquitin and the globular domain of the linker histone are comparable and one would expect an increased disorder upon ubiquitylation of the linker histone. However, the formation of higher order chromatin is not hindered and ubiquitylation of the linker histone may even promote gene expression. Structural data on chromatosomes is rare and HUb has never been modeled in a chromatosome so far. Descriptions of the chromatin complex with HUb would greatly benefit from computational structural data. In this study we generate molecular dynamics simulation data for six differently linked HUb variants with the help of a sampling scheme tailored to drive the exploration of phase space. We identify conformational sub-states of the six HUb variants using the sketch-map algorithm for dimensionality reduction and iterative HDBSCAN for clustering on the excessively sampled, shallow free energy landscapes. We present a highly efficient geometric scoring method to identify sub-states of HUb that fit into the nucleosome. We predict HUb conformations inside a nucleosome using on-dyad and off-dyad chromatosome structures as reference and show that unbiased simulations of HUb produce significantly more fitting than non-fitting HUb conformations. A tetranucleosome array is used to show that ubiquitylation can even occur in chromatin without too much steric clashes.Author summaryIn eukaryotic cells the linker histones play a crucial role in the formation of higher order nucleoprotein complex of DNA, especially for the arrangement of the nucleosomes. Histones can undergo several modifications, but modification of a linker histone with a single udiquitin (mono-ubiquitylation) remains one of the least understood epigenetic modifications. One reason is the inaccessibility of homogeneously modified linker histones for experimental methods, which are crucial for distinct studies. We combine molecular dynamics simulations with machine learning-based approaches to study the influence of mono-ubiquitylation in linker histones on DNA interaction and their ability to form higher order chromatin structures. We were able to determine the probable states in six differently linked histone-ubiquitin complexes via accelerating classical molecular dynamics simulations and using advanced state characterization techniques. As it is computationally unfeasible to simulate the whole chromatosome with different modified histones we developed efficient geometric scoring technique to select biologically relevant structures of all six mono-ubiquitylated linker histone that can bound to nucleosome.

Cytokeratin 10 (CK10) is a type I acidic low molecular weight cytokeratin which is mainly expressed in keratinizing squamous epithelium of the skin. Variable levels of CK10 protein have been described in squamous carcinomas of different sites and in some other epithelial neoplasms. To comprehensively determine the prevalence of CK10 expression in normal and neoplastic tissues, a tissue microarray containing 11,021 samples from 131 different tumor types and subtypes was analyzed by immunohistochemistry. CK10 immunostaining was detectable in 41 (31.3 %) of 131 tumor categories, including 18 (13.7 %) tumor types with at least one strongly positive case. The highest rate of positive staining was found in squamous cell carcinomas from various sites of origin (positive in 18.6 %-66.1 %) and in Warthin tumors of salivary glands (47.8 %), followed by various tumor entities known to potentially exhibit areas with squamous cell differentiation such as teratomas (33.3 %), basal cell carcinomas of the skin (14.3 %), adenosquamous carcinomas of the cervix (11.1 %), and several categories of urothelial neoplasms (3.1 %-16.8 %). In a combined analysis of 956 squamous cell carcinomas from 11 different sites of origin, reduced CK10 staining was linked to high grade (p 0.0001) and advanced stage (p = 0.0015) but unrelated to HPV infection. However, CK10 staining was not statistically related to grade (p = 0.1509) and recurrence-free (p = 0.5247) or overall survival (p = 0.5082) in 176 cervical squamous cell carcinomas. In the urinary bladder, CK10 staining occurred more commonly in muscle-invasive (17.7 %) than in non-invasive urothelial carcinomas (4.0 %-6.0 %; p 0.0001). In summary, our data corroborate a role of CK10 as a suitable marker for mature, keratinizing squamous cell differentiation in epithelial tissues. CK10 immunohistochemistry may thus be instrumental for a more objective evaluation of the clinical significance of focal squamous differentiation in cancer.

Aldoses and ketoses can glycate proteins yielding isomeric Amadori and Heyns products, respectively. Evidently, d-fructose is more involved in glycoxidation than d-glucose favoring the formation of advanced glycation endproducts (AGEs). While Amadori products and glucation have been studied extensively, the in vivo effects of fructation are largely unknown. The characterization of isomeric Amadori and Heyns peptides requires sufficient quantities of pure peptides. Thus, the glycated building block Nα-Fmoc-Lys[Nε-(2-deoxy-d-glucos-2-yl),Nε-Boc]-OH (Fmoc-Lys(Glc,Boc)-OH), which was synthesized in two steps starting from unprotected d-fructose and Fmoc-l-lysine hydrochloride, was site-specifically incorporated during solid-phase peptide synthesis. The building block allowed the synthesis of a peptide identified in tryptic digests of human serum albumin containing the reported glycation site at Lys233. The structure of the glycated amino acid derivatives and the peptide was confirmed by mass spectrometry and NMR spectroscopy. Importantly, the unprotected sugar moiety showed neither notable epimerization nor undesired side reactions during peptide elongation, allowing the incorporation of epimerically pure glucosyllysine. Upon acidic treatment, the building block as well as the resin-bound peptide formed one major byproduct due to incomplete Boc-deprotection, which was well separated by reversed-phase chromatography. Expectedly, the tandem mass spectra of the fructated amino acid and peptide were dominated by signals indicating neutral losses of 18, 36, 54, 84 and 96 m/z-units generating pyrylium and furylium ions.

Purpose Expansion of CD8+ cytotoxic Tlymphocytes is a prerequisite for anti-cancer immune activity and has gained interest in the era of immune checkpoint therapy. Methods To understand the CD8+ T cell dynamics in the tumor microenvironment, we used multiplex fluorescence immunohistochemistry to quantitate CD8+ proliferation (Ki67 co-expression) in tissue microarrays from 1107 colorectal, 642 renal cell, 1066 breast, 375 ovarian, 451 pancreatic and 347 gastric cancer samples. Results The density and the percentage of proliferating (Ki67+) CD8+ T cells were both highly variable between tumor types as well as between patients with the same tumor type. Elevated density and percentage of proliferating CD8+ cytotoxic T cells were significantly associated with favorable tumor parameters such as low tumor stage, negative nodal stage (p ≤ 0.0041 each), prolonged overall survival (p ≤ 0.0028 each) and an inflamed immune phenotype (p = 0.0025) in colorectal cancer and, in contrast, linked to high tumor stage, advanced ISUP/Fuhrman/Thoenes grading (each p ≤ 0.003), shorter overall survival (p ≤ 0.0330 each) and an immune inflamed phenotype (p = 0.0094) in renal cell cancer. In breast, ovarian, pancreatic and gastric cancer the role of (Ki67+)CD8+ Tcells was not linked to clinicopathological data. Conclusion Our data demonstrate a tumor type dependent prognostic impact of proliferating (Ki67+)CD8+ Tcells and an inverse impact in colorectal and renal cell cancer.

Different forms of life are known to express RNA ligases that catalyse the condensation of a 3’-hydroxy group and a 5’-terminal phosphate of RNA. No such RNA ligases have yet been identified in vertebrates. Here, we report that the hitherto uncharacterised human protein chromosome 12 open reading frame 29 (C12orf29), which we identified by a chemical proteomics approach, is a 5’-3’ RNA ligase. C12orf29 catalyses RNA ligation via auto-AMPylation of a critical lysine residue by using ATP as a cosubstrate and subsequent AMP transfer to the 5’-phosphate of an RNA substrate followed by phosphodiester bond formation. Studies at the cellular level reveal the involvement of C12orf29 in maintaining RNA integrity upon cellular stress induced by reactive oxygen species. These findings highlight the importance of RNA ligation for cellular fitness.