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Genomic instability in individuals with sex determination defects and germ cell cancer

The ability to transmit genetic information through generations depends on the preservation of genome integrity. Genetic abnormalities affect cell differentiation, causing tissue specification defects and cancer. We addressed genomic instability in individuals with Differences of Sex Development (DS...

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Autores principales: Krivega, Maria, Zimmer, Jutta, Slezko, Anna, Frank-Herrmann, Petra, Rehnitz, Julia, Hohenfellner, Markus, Bettendorf, Markus, Luzarowski, Marcin, Strowitzki, Thomas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10202957/
https://www.ncbi.nlm.nih.gov/pubmed/37217472
http://dx.doi.org/10.1038/s41420-023-01470-6
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author Krivega, Maria
Zimmer, Jutta
Slezko, Anna
Frank-Herrmann, Petra
Rehnitz, Julia
Hohenfellner, Markus
Bettendorf, Markus
Luzarowski, Marcin
Strowitzki, Thomas
author_facet Krivega, Maria
Zimmer, Jutta
Slezko, Anna
Frank-Herrmann, Petra
Rehnitz, Julia
Hohenfellner, Markus
Bettendorf, Markus
Luzarowski, Marcin
Strowitzki, Thomas
author_sort Krivega, Maria
collection PubMed
description The ability to transmit genetic information through generations depends on the preservation of genome integrity. Genetic abnormalities affect cell differentiation, causing tissue specification defects and cancer. We addressed genomic instability in individuals with Differences of Sex Development (DSD), characterized by gonadal dysgenesis, infertility, high susceptibility for different types of cancer, especially Germ Cell Tumors (GCT), and in men with testicular GCTs. Whole proteome analysis of leukocytes, supported by specific gene expression assessment, and dysgenic gonads characterization, uncovered DNA damage phenotypes with altered innate immune response and autophagy. Further examination of DNA damage response revealed a reliance on deltaTP53, which was compromised by mutations in the transactivation domain in DSD-individuals with GCT. Accordingly, drug-induced rescue of DNA damage was achieved by autophagy inhibition but not by stabilization of TP53 in DSD-individuals’ blood in vitro. This study elucidates possibilities for prophylactic treatments of DSD-individuals, as well as new diagnostic approaches of GCT.
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spelling pubmed-102029572023-05-24 Genomic instability in individuals with sex determination defects and germ cell cancer Krivega, Maria Zimmer, Jutta Slezko, Anna Frank-Herrmann, Petra Rehnitz, Julia Hohenfellner, Markus Bettendorf, Markus Luzarowski, Marcin Strowitzki, Thomas Cell Death Discov Article The ability to transmit genetic information through generations depends on the preservation of genome integrity. Genetic abnormalities affect cell differentiation, causing tissue specification defects and cancer. We addressed genomic instability in individuals with Differences of Sex Development (DSD), characterized by gonadal dysgenesis, infertility, high susceptibility for different types of cancer, especially Germ Cell Tumors (GCT), and in men with testicular GCTs. Whole proteome analysis of leukocytes, supported by specific gene expression assessment, and dysgenic gonads characterization, uncovered DNA damage phenotypes with altered innate immune response and autophagy. Further examination of DNA damage response revealed a reliance on deltaTP53, which was compromised by mutations in the transactivation domain in DSD-individuals with GCT. Accordingly, drug-induced rescue of DNA damage was achieved by autophagy inhibition but not by stabilization of TP53 in DSD-individuals’ blood in vitro. This study elucidates possibilities for prophylactic treatments of DSD-individuals, as well as new diagnostic approaches of GCT. Nature Publishing Group UK 2023-05-23 /pmc/articles/PMC10202957/ /pubmed/37217472 http://dx.doi.org/10.1038/s41420-023-01470-6 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Krivega, Maria
Zimmer, Jutta
Slezko, Anna
Frank-Herrmann, Petra
Rehnitz, Julia
Hohenfellner, Markus
Bettendorf, Markus
Luzarowski, Marcin
Strowitzki, Thomas
Genomic instability in individuals with sex determination defects and germ cell cancer
title Genomic instability in individuals with sex determination defects and germ cell cancer
title_full Genomic instability in individuals with sex determination defects and germ cell cancer
title_fullStr Genomic instability in individuals with sex determination defects and germ cell cancer
title_full_unstemmed Genomic instability in individuals with sex determination defects and germ cell cancer
title_short Genomic instability in individuals with sex determination defects and germ cell cancer
title_sort genomic instability in individuals with sex determination defects and germ cell cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10202957/
https://www.ncbi.nlm.nih.gov/pubmed/37217472
http://dx.doi.org/10.1038/s41420-023-01470-6
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