Cargando…
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...
Autores principales: | , , , , , , , , |
---|---|
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 |
_version_ | 1785045529936265216 |
---|---|
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. |
format | Online Article Text |
id | pubmed-10202957 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT krivegamaria genomicinstabilityinindividualswithsexdeterminationdefectsandgermcellcancer AT zimmerjutta genomicinstabilityinindividualswithsexdeterminationdefectsandgermcellcancer AT slezkoanna genomicinstabilityinindividualswithsexdeterminationdefectsandgermcellcancer AT frankherrmannpetra genomicinstabilityinindividualswithsexdeterminationdefectsandgermcellcancer AT rehnitzjulia genomicinstabilityinindividualswithsexdeterminationdefectsandgermcellcancer AT hohenfellnermarkus genomicinstabilityinindividualswithsexdeterminationdefectsandgermcellcancer AT bettendorfmarkus genomicinstabilityinindividualswithsexdeterminationdefectsandgermcellcancer AT luzarowskimarcin genomicinstabilityinindividualswithsexdeterminationdefectsandgermcellcancer AT strowitzkithomas genomicinstabilityinindividualswithsexdeterminationdefectsandgermcellcancer |