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ADAR1 Regulates Alternative Splicing Through an RNA Editing-Independent Mechanism
(MDPI AG, 2026-04-29)
Eduardo A. Sagredo
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Victor Karlström
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Alejandro Blanco
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Paloma Moraga
;
Matias Vergara
<jats:p>Dysregulation of the RNA-editing enzyme ADAR1 is associated with human diseases, including cancer, but its RNA-editing-independent roles in alternative splicing remain largely unexplored. Comprehending these molecular mechanisms is paramount, as they may unveil novel therapeutic targets. This study elucidates how the ADAR1p110 isoform influences alternative splicing independently of its canonical editing activity. Employing RNA-sequencing, proteomic analysis of ADAR1p110 interactors, and functional assays with wild-type and mutant ADAR1 in diverse human cell lines (including cancer models), we investigated its impact on the splicing landscape. Our findings indicate that ADAR1p110 interacts with pivotal spliceosome components and auxiliary splicing regulators. Notably, ADAR1 extensively modulates alternative-splicing events, with most of these alterations occurring independently of its RNA-editing activity and often its RNA-binding capacity. Furthermore, ADAR1 alters the isoform expression of other splicing factors (e.g., ACIN1), suggesting an indirect regulatory mechanism. Importantly, this splicing reprogramming affects genes that govern therapeutic response, positioning the ADAR-splicing axis as a potential driver of drug resistance. By revealing this predominantly editing-independent mechanism, we expand the understanding of ADAR1’s non-canonical functions and identify a new avenue for therapeutic intervention in cancer.</jats:p>
2
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DNA damage and cell death induced by exposure to ultra-high dose rate low-dose pulsed X-rays emitted from a kilojoule plasma focus device
(Springer Science and Business Media LLC, 2026-03-10)
Héctor Araya
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Jalaj Jain
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Rodrigo Andaur
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José Moreno
;
Sergio Davis
2
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Abstract 6440: Effects of cumulative tobacco exposure on lung cancer genomic profiles in Latin Americans
(American Association for Cancer Research (AACR), 2026-04-03)
Javiera Garrido
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Evelin González
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Alejandro Blanco
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Gonzalo Sepúlveda-Hermosilla
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Matias Freire
<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Motivation:</jats:title> <jats:p>Tobacco exposure is a major determinant of tumor genomic landscapes in non-small cell lung cancer (NSCLC). Two of the most clinically relevant actionable genes in lung cancer, EGFR and KRAS, show opposite patterns, with smokers exhibiting a higher prevalence of alterations in KRAS and never-smokers in EGFR. Yet, the dynamic and evolution of genomic changes as a function of cumulative tobacco exposure has received limited attention. Here, we examine how tumor genomic profiles vary according to smoking intensity, duration, and time since cessation (TSC). Our study focuses on an underrepresented population of Latin American patients, where additional research is needed to better characterize tumor heterogeneity.</jats:p> </jats:sec> <jats:sec> <jats:title>Methodology:</jats:title> <jats:p>The population was obtained from the protocol Characterization and Validation of Molecular Diagnostic Technologies for Lung Cancer Patients from Chile, Brazil, and Peru. Participant recruitment was between July 2015 and October 2018 across 37 different centers. Primary or metastatic NSCLC specimens were analyzed, and genomic profiles were generated with the Oncomine Focus Assay (OFA). A total of 1,864 participants yielded QC-approved genomic profiles. Covariates of interest were assessed at enrollment. Cumulative tobacco exposure, including smoking intensity (cigarettes per day), duration, and TSC, was quantified using the Comprehensive Smoking Index (CSI). In addition, smoking status (current vs. never) was recoded as a function of TSC in order to identify the time period during which major genomic alterations (GA) are most likely to occur. Descriptive statistics, generalized linear models, and generalized additive models were used to evaluate the association between CSI and the prevalence of GA across genes. All models were adjusted for potential confounders, including country, age, sex, NSCLC subtype, cancer stage and history of cancer.</jats:p> </jats:sec> <jats:sec> <jats:title>Results and Conclusions:</jats:title> <jats:p>A total of 1100 patients had complete genomic and tobacco exposure information. Among current smokers, median smoking intensity and duration were 20 cigarettes per day and 48 years, respectively, compared with 30 cigarettes per day and 47 years among former smokers. Ninety percent of former smokers had ceased tobacco use at least 10 years prior to diagnosis, with a median TSC of 1 year. CSI analysis identified 14 genes significantly associated with genomic alteration status, including EGFR, PIK3CA, ALK, MTOR, ERBB3, and RET. Higher CSI values (4th quartile) showed approximately double the frequency of genomic alterations compared with the lowest CSI quartile for ALK (16.2% vs. 8.7%), RET (12.8% vs. 6.9%), and MTOR (15% vs. 6.9%). Mid-range CSI values exhibited the lowest prevalence of alterations in EGFR (12.6% vs. 31%) and PIK3CA (6.9% vs. 14.5%). Overall, these findings support the value of CSI in refining exposure-genotype associations and the need for improves risk stratification efforts in diverse populations.</jats:p> </jats:sec> <jats:sec> <jats:title>Citation Format:</jats:title> <jats:p>Javiera Garrido, Evelin González, Alejandro Blanco, Gonzalo Sepúlveda-Hermosilla, Matias Freire, Solange Rivas, Katherine Marcelain, Gareth I. Owen, Carolina Ibañez, Alejandro H. Corvalan, Marcelo Garrido, Rodrigo Assar, Rodrigo Lizana, Javier Cáceres-Molina, Diego Ampuero, Liliana Ramos, Paola Pérez, Osvaldo Aren, Sara Chernilo, Cristina Fernández, María Loreto Spencer, Jacqueline Flores, Giuliano Bernal, Mónica Ahumada Olea, Germán Rasse, Carolina Sánchez, Maria Galli de Amorim, Emmanuel Dias-Neto, Helano C. Freitas, Ricardo Armisen. Effects of cumulative tobacco exposure on lung cancer genomic profiles in Latin Americans [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6440.</jats:p> </jats:sec>
2
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Transcription-Coupled Repair Promotes the Retention of Mutations in Coding Regions During Replication Stress
(MDPI AG, 2026-01-23)
Evelyn Zambrano
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Cristopher Fierro
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Fernanda Morales
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Marcia Manterola
;
Arnaldo Marin
Replication stress (RS) is a primary driver of genomic instability in cancer, yet the contribution of transcription-coupled repair (TC-NER) to this process remains unclear. Here, we investigate how the TC-NER factor ERCC6 (CSB) shapes mutational landscapes under RS. We found that ERCC6 deficiency biases early damage signaling toward a 53BP1-mediated response, ultimately leading to senescence. Conversely, ERCC6-proficient cells prioritize survival and proliferative recovery but at the expense of distinct genomic alterations. Whole-exome sequencing reveals that ERCC6 proficiency is associated with the retention of stress-induced mutations specifically within coding regions of transcriptionally active loci, whereas ERCC6-deficient cells accumulate variants primarily in intergenic regions. These findings suggest that while ERCC6 safeguards transcriptional continuity during RS, its activity is associated with a biased retention of stress-induced mutations within coding regions in the surviving cell population. These findings reveal a previously unrecognized link between transcription-coupled repair and mutation distribution in human cells, linking TC-NER to context-dependent somatic evolution and tumor heterogeneity.
18
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Cryopreserved Total Skin Allografts From Living Donors for Complex Wound Management: A New Paradigm in Regenerative Wound Care
(Wiley, 2025-09)
Marcelo Fonseca
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Aldo Cañete
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Luana Mandriaza
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Jennifer Gómez
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Jaume Masiá
<jats:title>ABSTRACT</jats:title><jats:p>Skin allografts are essential in managing complex wounds, yet their availability is limited by low post‐mortem donation rates. Skin harvested during body contouring surgeries offers a novel and sustainable source to expand tissue supply. We conducted a retrospective descriptive study at the Tarapacá Skin and Tissue Bank from January 2022 to December 2024. All donations from body contouring surgeries were processed as cryopreserved total skin allografts following national tissue banking standards. Variables included donor demographics, harvested area, units produced, microbiological results, and discard rates. To describe clinical performance, we present our group's initial clinical series of treated patients. From 248 living donors (mean age 41.3 years), 81 293 cm<jats:sup>2</jats:sup> of skin generated 2050 units. The discard rate was 27%, mainly due to a storage failure and isolated microbial contamination. Clinically, all patients achieved complete initial graft take, followed by gradual necrotic eschar formation at an average of 21 days. Eschar removal revealed vital tissue firmly adhered to the recipient bed, rich in fibroblasts and neovascular structures. Subsequent management included either escharectomy with split‐thickness autografting over the neodermis, or spontaneous eschar lysis and skin regeneration, with the graft functioning as a dermal regenerator. This model increases tissue availability while providing allografts with both coverage and dermal regenerative properties.</jats:p>
1Scopus© Citations 2
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The mutational landscape and actionable targets of gallbladder cancer: an ancestry-informed and comparative analysis of a Chilean population
(Frontiers Media SA, 2025-10-03)
José Ignacio Erices
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Evelin González
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Marcela Salgado
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Carol Barahona-Ponce
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Matías Freire
1
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Data Resource Profile: EULAT Eradicate GBC: the European-Latin American Research Consortium towards Eradication of Preventable Gallbladder Cancer
(Oxford University Press (OUP), 2025-06-11)
Dominique Scherer
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Carol Barahona Ponce
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Claudio Mengoa
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Paola Montenegro
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Hector Losada
Scopus© Citations 1 2
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International collaborative research to improve gallbladder cancer prevention
(Springer Science and Business Media LLC, 2025-04-04)
Dominique Scherer
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Rajiv Kumar
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Justo Lorenzo Bermejo
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Carol Barahona Ponce
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Claudio Mengoa
1
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SKI regulates rRNA transcription and pericentromeric heterochromatin to ensure centromere integrity and genome stability
(Elsevier BV, 2025-09)
Víctor Pola-Véliz
;
David Carrero
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Eduardo A. Sagredo
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Víctor Inostroza
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Claudio Cappelli
1
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From cadaveric donation to cryopreserved total skin allografts: Transforming the Chilean skin donation model
(Elsevier BV, 2025-08)
Marcelo Fonseca
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Aldo Cañete
;
Luana Mandriaza
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Jennifer Gómez
;
Jaume Masiá
2

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