DataSheet1_A Novel Ferroptosis-Related lncRNA Prognostic Model and Immune Infiltration Features in Skin Cutaneous Melanoma.ZIP

Background: Skin cutaneous melanoma (SKCM) is an aggressive malignant skin tumor. Ferroptosis is an iron-dependent cell death that may mobilize tumor-infiltrating immunity against cancer. The potential mechanism of long non-coding RNAs (lncRNAs) in ferroptosis in SKCM is not clear. In this study, the prognostic and treatment value of ferroptosis-related lncRNAs was explored in SKCM, and a prognostic model was established.Methods: We first explored the mutation state of ferroptosis-related genes in SKCM samples from The Cancer Genome Atlas database. Then, we utilized consensus clustering analysis to divide the samples into three clusters based on gene expression and evaluated their immune infiltration using gene-set enrichment analysis (GSEA) ESTIMATE and single-sample gene-set enrichment analysis (ssGSEA) algorithms. In addition, we applied univariate Cox analysis to screen prognostic lncRNAs and then validated their prognostic value by Kaplan–Meier (K-M) and transcripts per kilobase million (TPM) value analyses. Finally, we constructed an 18-ferroptosis-related lncRNA prognostic model by multivariate Cox analysis, and SKCM patients were allocated into different risk groups based on the median risk score. The prognostic value of the model was evaluated by K-M and time-dependent receiver operating characteristic (ROC) analyses. Additionally, the immunophenoscore (IPS) in different risk groups was detected.Results: The top three mutated ferroptosis genes were TP53, ACSL5, and TF. The SKCM patients in the cluster C had the highest ferroptosis-related gene expression with the richest immune infiltration. Based on the 18 prognosis-related lncRNAs, we constructed a prognostic model of SKCM patients. Patients at low risk had a better prognosis and higher IPS.Conclusion: Our findings revealed that ferroptosis-related lncRNAs were expected to become potential biomarkers and indicators of prognosis and immunotherapy treatment targets of SKCM.</p

Contains supporting figures.

The catalytic (CAT) domain is a key region of poly (ADP-ribose) polymerase 1 (PARP1), which has crucial interactions with inhibitors, DNA, and other domains of PARP1. To facilitate the development of potential inhibitors of PARP1, it is of great significance to clarify the differences in structural dynamics and key residues between CAT/inhibitors and DNA/PARP1/inhibitors through structure-based computational design. In this paper, conformational changes in PAPR1 and differences in key residue interactions induced by inhibitors were revealed at the molecular level by comparative molecular dynamics (MD) simulations and energy decomposition. On one hand, PARP1 inhibitors indirectly change some residues of the CAT domain which interact with DNA and other domains. Furthermore, the interaction between ligands and catalytic binding sites can be transferred to the DNA recognition domain of PARP1 by a strong negative correlation movement among multi-domains of PARP1. On the other hand, it is not reliable to use the binding energy of CAT/ligand as a measure of ligand activity, because it may in some cases differs greatly from the that of PARP1/DNA/ligand. For PARP1/DNA/ligand, the stronger the binding stability between the ligand and PARP1, the stronger the binding stability between PARP1 and DNA. The findings of this work can guide further novel inhibitor design and the structural modification of PARP1 through structure-based computational design.</div

Fig 2 -

(a) Per-residue RMSFs for ZnF1 in Model 1 to Model 4. (b) The three-dimensional structure diagram of ZnF1 (4OPX). The interaction interface of ZnF1/DSB and ZnF1/CAT are represented by blue and red, respectively, and the corresponding residues are shown in blue and red. (c) Per-residue energy contribution spectra of ZnF1 on the surface of ZnF1/DSB for Model 1 to Model 4. Red, blue, green, and yellow bars represent Lig1, Lig2, Lig3, and without ligand binding to CAT (marked as WLig). (d) Per-residue energy contribution spectra of ZnF1 on the surface of ZnF1/CAT for Model 1 to Model 4. Red, blue, green, and yellow bars represent Lig1, Lig2, Lig3, and WLig.</p

The calculated (MM/GBSA) binding free energies of ZnF1/CAT.

The calculated (MM/GBSA) binding free energies of ZnF1/CAT.</p

Schematic diagram of binding mechanisms among ligands, CAT, ZnF1, ZnF3 and DSB (4OPX).

CAT area includes WGR (green cartoon), HD (red cartoon) and ART (blue cartoon). (a) Interaction between ligand and CAT. (b) Interaction between ZnF1 and CAT. (c) Interaction between ZnF3 and CAT. (d) Interaction between DSB and CAT. (e) Interaction between ZnF1 and DSB. (f) Interaction between ZnF3 and DSB. (g) Interaction between ZnF1 and ZnF3.</p

The calculated (MMGBSA) binding free energies of the ZnF1/DSB for Model 1 to Model 4.

The calculated (MMGBSA) binding free energies of the ZnF1/DSB for Model 1 to Model 4.</p

The calculated (MMGBSA) binding free energies of DSB/CAT.

The calculated (MMGBSA) binding free energies of DSB/CAT.</p

Fig 1 -

(a) Three-dimensional diagram of the binding system (4OPX). ZnF1, ZnF3 and CAT (including WGR) are depicted in red, yellow, and green, respectively. DSB is depicted in blue. Ligand is shown in purple stick model. (b) Two-dimensional diagram of C10H10FNO2, marked as Lig1. (c) Two-dimensional diagram of C16H11NO5, marked as Lig2. (c) Two-dimensional diagram of C22H22N2O5, marked as Lig3.</p

The calculated (MMGBSA) binding free energies of ZnF3/CAT.

The calculated (MMGBSA) binding free energies of ZnF3/CAT.</p

Fig 3 -

(a) Per-residue RMSFs for ZnF 3 in Model 1 to Model 4. (b) The three-dimensional structure diagram of ZnF3 (4OPX). The interaction interfaces of ZnF3/DSB and ZnF3/CAT are represented by blue and red, respectively, and the corresponding residues are shown in blue and red. (c) Per-residue energy contribution spectra of ZnF3 on the surface of ZnF3/DSB. Red, blue, green, and yellow bars represent Lig1, Lig2, Lig3, and WLig. (d) Per-residue energy contribution spectra of ZnF3 on the surface of ZnF3/CAT. Red, blue, green, and yellow bars represent Lig1, Lig2, Lig3, and WLig.</p