Differential Effects of Biomimetic Thymine Dimers and Corresponding Photo-Adducts in Primary Human Keratinocytes and Fibroblasts
UVB radiation induces DNA damage generating several thymine photo-adducts (TDPs), which can lead to mutations and cellular transformation. The DNA repair pathways preserve genomic stability by recognizing and removing photodamage. These DNA repair side products may affect cellular processes. We prev...
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2024-11-01
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| author | Rosanna Monetta Denise Campagna Valeria Bartolocci Alessio Capone Massimo Teson Silvia Filippi Sofia Gabellone Davide Piccinino Raffaele Saladino Elena Dellambra |
| author_facet | Rosanna Monetta Denise Campagna Valeria Bartolocci Alessio Capone Massimo Teson Silvia Filippi Sofia Gabellone Davide Piccinino Raffaele Saladino Elena Dellambra |
| author_sort | Rosanna Monetta |
| collection | DOAJ |
| description | UVB radiation induces DNA damage generating several thymine photo-adducts (TDPs), which can lead to mutations and cellular transformation. The DNA repair pathways preserve genomic stability by recognizing and removing photodamage. These DNA repair side products may affect cellular processes. We previously synthesized novel thymine biomimetic thymine dimers (BTDs) bearing different alkane spacers between nucleobases. Thus, the present study investigates whether novel BTDs and their TDPs can modulate DNA damage safeguard pathways of primary keratinocytes and fibroblasts using 2D and 3D models. We found that the p53/p21<sup>waf1</sup> pathway is activated by BTDs and TDPs in primary cells similar to UVB exposure. Compound <b>1b</b> can also induce the p53/p21<sup>waf1</sup> pathway in a 3D skin model. However, BTDs and TDPs exhibit distinct effects on cell survival. They have a protective action in keratinocytes, which maintain their clonogenic ability following treatments. Conversely, compounds induce pro-apoptotic pathways in fibroblasts that exhibit reduced clonogenicity. Moreover, compounds induce inflammatory cytokines mainly in keratinocytes rather than fibroblasts. Matrix metalloproteinase 1 is up-regulated in both cell types after treatments. Therefore, BTDs and TDPs can act in the short term as safeguard mechanisms helping DNA damage response. Furthermore, they have distinct biological effects depending on photodamage form and cell type. |
| format | Article |
| id | doaj-art-2c8a8552983e4bb4ac75335fbd26dfe3 |
| institution | DOAJ |
| issn | 2218-273X |
| language | English |
| publishDate | 2024-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj-art-2c8a8552983e4bb4ac75335fbd26dfe32025-08-20T02:53:18ZengMDPI AGBiomolecules2218-273X2024-11-011412148410.3390/biom14121484Differential Effects of Biomimetic Thymine Dimers and Corresponding Photo-Adducts in Primary Human Keratinocytes and FibroblastsRosanna Monetta0Denise Campagna1Valeria Bartolocci2Alessio Capone3Massimo Teson4Silvia Filippi5Sofia Gabellone6Davide Piccinino7Raffaele Saladino8Elena Dellambra9Laboratory of Molecular and Cell Biology, Istituto Dermopatico Dell’Immacolata (IDI-IRCCS), 00167 Rome, ItalyLaboratory of Molecular and Cell Biology, Istituto Dermopatico Dell’Immacolata (IDI-IRCCS), 00167 Rome, ItalyLaboratory of Molecular and Cell Biology, Istituto Dermopatico Dell’Immacolata (IDI-IRCCS), 00167 Rome, ItalyLaboratory of Molecular and Cell Biology, Istituto Dermopatico Dell’Immacolata (IDI-IRCCS), 00167 Rome, ItalyLaboratory of Molecular and Cell Biology, Istituto Dermopatico Dell’Immacolata (IDI-IRCCS), 00167 Rome, ItalyLaboratorio di Genetica dell’Invecchiamento, Dipartimento di Scienze Ecologiche e Biologiche, Università degli Studi della Tuscia, Largo dell’Università snc, 01100 Viterbo, ItalyIRCCS Istituto Romagnolo per lo Studio dei Tumori “Dino Amadori”—IRST Srl, 47014 Meldola, ItalyCentro Integrato di Ateneo, Sezione Centro Grandi Attrezzature, Università degli Studi della Tuscia, Largo dell’Università snc, 01100 Viterbo, ItalyDipartimento di Scienze Ecologiche e Biologiche, Università degli Studi della Tuscia, Via S Camillo de Lellis, 01100 Viterbo, ItalyLaboratory of Molecular and Cell Biology, Istituto Dermopatico Dell’Immacolata (IDI-IRCCS), 00167 Rome, ItalyUVB radiation induces DNA damage generating several thymine photo-adducts (TDPs), which can lead to mutations and cellular transformation. The DNA repair pathways preserve genomic stability by recognizing and removing photodamage. These DNA repair side products may affect cellular processes. We previously synthesized novel thymine biomimetic thymine dimers (BTDs) bearing different alkane spacers between nucleobases. Thus, the present study investigates whether novel BTDs and their TDPs can modulate DNA damage safeguard pathways of primary keratinocytes and fibroblasts using 2D and 3D models. We found that the p53/p21<sup>waf1</sup> pathway is activated by BTDs and TDPs in primary cells similar to UVB exposure. Compound <b>1b</b> can also induce the p53/p21<sup>waf1</sup> pathway in a 3D skin model. However, BTDs and TDPs exhibit distinct effects on cell survival. They have a protective action in keratinocytes, which maintain their clonogenic ability following treatments. Conversely, compounds induce pro-apoptotic pathways in fibroblasts that exhibit reduced clonogenicity. Moreover, compounds induce inflammatory cytokines mainly in keratinocytes rather than fibroblasts. Matrix metalloproteinase 1 is up-regulated in both cell types after treatments. Therefore, BTDs and TDPs can act in the short term as safeguard mechanisms helping DNA damage response. Furthermore, they have distinct biological effects depending on photodamage form and cell type.https://www.mdpi.com/2218-273X/14/12/1484thymine dimerskeratinocytesfibroblastsskinUVB radiation |
| spellingShingle | Rosanna Monetta Denise Campagna Valeria Bartolocci Alessio Capone Massimo Teson Silvia Filippi Sofia Gabellone Davide Piccinino Raffaele Saladino Elena Dellambra Differential Effects of Biomimetic Thymine Dimers and Corresponding Photo-Adducts in Primary Human Keratinocytes and Fibroblasts Biomolecules thymine dimers keratinocytes fibroblasts skin UVB radiation |
| title | Differential Effects of Biomimetic Thymine Dimers and Corresponding Photo-Adducts in Primary Human Keratinocytes and Fibroblasts |
| title_full | Differential Effects of Biomimetic Thymine Dimers and Corresponding Photo-Adducts in Primary Human Keratinocytes and Fibroblasts |
| title_fullStr | Differential Effects of Biomimetic Thymine Dimers and Corresponding Photo-Adducts in Primary Human Keratinocytes and Fibroblasts |
| title_full_unstemmed | Differential Effects of Biomimetic Thymine Dimers and Corresponding Photo-Adducts in Primary Human Keratinocytes and Fibroblasts |
| title_short | Differential Effects of Biomimetic Thymine Dimers and Corresponding Photo-Adducts in Primary Human Keratinocytes and Fibroblasts |
| title_sort | differential effects of biomimetic thymine dimers and corresponding photo adducts in primary human keratinocytes and fibroblasts |
| topic | thymine dimers keratinocytes fibroblasts skin UVB radiation |
| url | https://www.mdpi.com/2218-273X/14/12/1484 |
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