Biology subjects

Cicconi, A.

Publications and source records attributed to Cicconi, A..

3 recordsLinked to original sources

bioRxiv2025

Genotype by Environment Interaction influenced the content of crude protein and total amino acids in lentil varieties

Lentil (Lens culinaris Medik) is a globally important grain legume valued for its high protein content and nutritional quality. However, the genetic and environmental factors influencing protein and amino acid composition, particularly the role of genotype x environment interaction (GEI), remain partially uncovered. This study evaluated 15 diverse lentil genotypes across seven agronomic trials spanning multiple years, sowing seasons, and locations to assess the effects of genotype, environment, and GEI on crude protein (CP), crude protein yield (CPY), total amino acids (TAA), and total amino acid yield (TAAY). Advanced statistical models such as AMMI, GGE, and WAASB were employed to dissect the contributions of genetic and environmental components and to identify stable, high-performing genotypes. Results revealed significant phenotypic variation for CP, Amino Acids (AA), and TAA among genotypes. Seasonal variation, especially between autumn and spring sowings, was the primary environmental driver of GEI for both CP and CPY. Notably, some landraces (PI_431710_LSP, PI_431739_LSP, PI_431753_LSP, IG_1959) demonstrated both high productivity and stability across environments, while others excelled in specific mega-environments identified through GGE analysis. Our findings emphasize the importance of integrating into lentil breeding programs, stability and adaptability, and a more comprehensive approach to measure the yield (e.g., CPY, MegaJoule, ammino acid composition and TAAY), which takes into account the quality and the effective energetic production of a crop. From this perspective, we highlight landraces as valuable sources of genetic diversity for improving yield. This work provides a foundation for targeted breeding strategies aimed at developing lentil varieties with enhanced protein content, balanced amino acid profiles, and resilience to environmental variability

genetics↗

bioRxiv2025

SHLD2 loss is a synthetic vulnerability to Polθ inhibition combined with radiotherapy

DNA polymerase theta (Pol{theta}) plays a crucial role in the repair of DNA double-strand breaks (DSBs) by microhomology-mediated end joining (MMEJ). We previously demonstrated that Pol{theta} inhibition (Pol{theta}i) is an effective and well-tolerated approach to sensitise tumours to radiotherapy (RT). Here, we profiled 54 cancer cell lines and found that Pol{theta}i induces significant radiosensitisation in most models, though with marked variability not explained by indicators of Pol{theta} activity. To pinpoint molecular determinants of radiosensitisation by Pol{theta}i, we performed a CRISPR knockout screen which revealed loss of the TP53BP1/Shieldin pathway component SHLD2 (FAM35A) as a vulnerability to Pol{theta}i combined with RT. We demonstrated that SHLD2 loss not only increases sensitivity to RT alone, but also enhances the radiosensitising effect of Pol{theta}i, both in vitro and in vivo. Importantly, we found that SHLD2 is deleted in a subset of human prostate cancers, often co-occurring with PTEN loss, an adverse prognostic factor. Furthermore, we show that SHLD2-deficient cancer cells are more reliant on Pol{theta} to prevent DSB accumulation and chromosomal instability. In summary, we discovered SHLD2 loss as a novel collateral vulnerability that can be exploited through combined treatment with Pol{theta}i and RT.

cancer biology↗

bioRxiv2022

Small-molecule Polθ inhibitors provide safe and effective tumor radiosensitization in preclinical models

DNA polymerase theta (Pol{theta}) is a DNA repair enzyme critical for microhomology mediated end joining (MMEJ). Pol{theta} has limited expression in normal tissues but is frequently overexpressed in cancer cells and, therefore, represents an ideal target for tumor-specific radiosensitization. Here, we show that ART558 and ART899, two novel and specific allosteric inhibitors of the Pol{theta} DNA polymerase domain, potently radiosensitize tumor cells, particularly when combined with fractionated radiation. Importantly, normal fibroblasts are not radiosensitized by Pol{theta} inhibition. Mechanistically, we show that the radiosensitization caused by Pol{theta} inhibition is most effective in replicating cells and is due to impaired DNA damage repair. We also show that radiosensitization is still effective under hypoxia, suggesting that these inhibitors may help overcome hypoxia-induced radioresistance. In addition, we describe for the first time ART899 and characterize it as a potent and specific Pol{theta} inhibitor with improved metabolic stability. In vivo, the combination of Pol{theta} inhibition using ART899 with fractionated radiation is well tolerated and results in a significant reduction in tumor growth compared to radiation alone. These results pave the way for future clinical trials of Pol{theta} inhibitors in combination with radiotherapy.

cancer biology↗