A computational and structural analysis of germline and somatic variants affecting the DDR mechanism, and their impact on human diseases

Abstract DNA-Damage Response (DDR) proteins are crucial for maintaining the integrity of the genome by identifying and repairing errors in DNA. Variants affecting their function can have severe consequences since failure to repair damaged DNA can result in cells turning cancerous. Here, we compare g...

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Autores principales:	Lorena Magraner-Pardo, Roman A. Laskowski, Tirso Pons, Janet M. Thornton
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/b3eee09f8ac742dab50ee895bf220e71
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spelling	oai:doaj.org-article:b3eee09f8ac742dab50ee895bf220e712021-12-02T16:08:05ZA computational and structural analysis of germline and somatic variants affecting the DDR mechanism, and their impact on human diseases10.1038/s41598-021-93715-62045-2322https://doaj.org/article/b3eee09f8ac742dab50ee895bf220e712021-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-93715-6https://doaj.org/toc/2045-2322Abstract DNA-Damage Response (DDR) proteins are crucial for maintaining the integrity of the genome by identifying and repairing errors in DNA. Variants affecting their function can have severe consequences since failure to repair damaged DNA can result in cells turning cancerous. Here, we compare germline and somatic variants in DDR genes, specifically looking at their locations in the corresponding three-dimensional (3D) structures, Pfam domains, and protein–protein interaction interfaces. We show that somatic variants in metastatic cases are more likely to be found in Pfam domains and protein interaction interfaces than are pathogenic germline variants or variants of unknown significance (VUS). We also show that there are hotspots in the structures of ATM and BRCA2 proteins where pathogenic germline, and recurrent somatic variants from primary and metastatic tumours, cluster together in 3D. Moreover, in the ATM, BRCA1 and BRCA2 genes from prostate cancer patients, the distributions of germline benign, pathogenic, VUS, and recurrent somatic variants differ across Pfam domains. Together, these results provide a better characterisation of the most recurrent affected regions in DDRs and could help in the understanding of individual susceptibility to tumour development.Lorena Magraner-PardoRoman A. LaskowskiTirso PonsJanet M. ThorntonNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-17 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Lorena Magraner-Pardo Roman A. Laskowski Tirso Pons Janet M. Thornton A computational and structural analysis of germline and somatic variants affecting the DDR mechanism, and their impact on human diseases
description	Abstract DNA-Damage Response (DDR) proteins are crucial for maintaining the integrity of the genome by identifying and repairing errors in DNA. Variants affecting their function can have severe consequences since failure to repair damaged DNA can result in cells turning cancerous. Here, we compare germline and somatic variants in DDR genes, specifically looking at their locations in the corresponding three-dimensional (3D) structures, Pfam domains, and protein–protein interaction interfaces. We show that somatic variants in metastatic cases are more likely to be found in Pfam domains and protein interaction interfaces than are pathogenic germline variants or variants of unknown significance (VUS). We also show that there are hotspots in the structures of ATM and BRCA2 proteins where pathogenic germline, and recurrent somatic variants from primary and metastatic tumours, cluster together in 3D. Moreover, in the ATM, BRCA1 and BRCA2 genes from prostate cancer patients, the distributions of germline benign, pathogenic, VUS, and recurrent somatic variants differ across Pfam domains. Together, these results provide a better characterisation of the most recurrent affected regions in DDRs and could help in the understanding of individual susceptibility to tumour development.
format	article
author	Lorena Magraner-Pardo Roman A. Laskowski Tirso Pons Janet M. Thornton
author_facet	Lorena Magraner-Pardo Roman A. Laskowski Tirso Pons Janet M. Thornton
author_sort	Lorena Magraner-Pardo
title	A computational and structural analysis of germline and somatic variants affecting the DDR mechanism, and their impact on human diseases
title_short	A computational and structural analysis of germline and somatic variants affecting the DDR mechanism, and their impact on human diseases
title_full	A computational and structural analysis of germline and somatic variants affecting the DDR mechanism, and their impact on human diseases
title_fullStr	A computational and structural analysis of germline and somatic variants affecting the DDR mechanism, and their impact on human diseases
title_full_unstemmed	A computational and structural analysis of germline and somatic variants affecting the DDR mechanism, and their impact on human diseases
title_sort	computational and structural analysis of germline and somatic variants affecting the ddr mechanism, and their impact on human diseases
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/b3eee09f8ac742dab50ee895bf220e71
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A computational and structural analysis of germline and somatic variants affecting the DDR mechanism, and their impact on human diseases

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