A truncating variant of RAD51B associated with primary ovarian insufficiency provides insights into its meiotic and somatic functions

[EN]Primary ovarian insufficiency (POI) causes female infertility by abolishing normal ovarian function. Although its genetic etiology has been extensively investigated, most POI cases remain unexplained. Using whole-exome sequencing, we identified a homozygous variant in RAD51B -(c.92delT) in two s...

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Autores: Franca, Monica M, Condezo, Yazmine B, Elzaiat, Maëva, Felipe-Medina, Natalia, Sánchez Sáez, Fernando, Muñoz, Sergio, Sainz-Urruela, Raquel, Martín-Hervás, M Rosario, García-Valiente, Rodrigo, Sánchez Martín, Manuel Adolfo, Astudillo, Aurora, Mendez, Juan, Llano Cuadra, María Elena, Veitia, Reiner A, Mendonca, Berenice B, Pendás, Alberto M
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2022
País:España
Institución:Universidad de Salamanca (USAL)
Repositorio:GREDOS. Repositorio Institucional de la Universidad de Salamanca
OAI Identifier:oai:gredos.usal.es:10366/169196
Acceso en línea:http://hdl.handle.net/10366/169196
Access Level:acceso abierto
Palabra clave:Meiosis
POI fertility
DNA repair
Chromosome Aberrations
DNA Repair
Primary Ovarian Insufficiency
Fibroblasts
DNA-Binding Proteins
Humans
Mice
2407 Biología Celular
2411.16 Fisiología de la Reproducción
fibroblastos
meiosis
insuficiencia ovárica primaria
humanos
ratones
proteínas de unión al ADN
aberraciones cromosómicas
reparación del ADN
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repository_id_str
spelling A truncating variant of RAD51B associated with primary ovarian insufficiency provides insights into its meiotic and somatic functionsFranca, Monica MCondezo, Yazmine BElzaiat, MaëvaFelipe-Medina, NataliaSánchez Sáez, FernandoMuñoz, SergioSainz-Urruela, RaquelMartín-Hervás, M RosarioGarcía-Valiente, RodrigoSánchez Martín, Manuel AdolfoAstudillo, AuroraMendez, JuanLlano Cuadra, María ElenaVeitia, Reiner AMendonca, Berenice BPendás, Alberto MMeiosisPOI fertilityDNA repairChromosome AberrationsDNA RepairMeiosisPrimary Ovarian InsufficiencyFibroblastsDNA-Binding ProteinsHumansMice2407 Biología Celular2411.16 Fisiología de la Reproducciónfibroblastosmeiosisinsuficiencia ovárica primariahumanosratonesproteínas de unión al ADNaberraciones cromosómicasreparación del ADN[EN]Primary ovarian insufficiency (POI) causes female infertility by abolishing normal ovarian function. Although its genetic etiology has been extensively investigated, most POI cases remain unexplained. Using whole-exome sequencing, we identified a homozygous variant in RAD51B -(c.92delT) in two sisters with POI. In vitro studies revealed that this variant leads to translation reinitiation at methionine 64. Here, we show that this is a pathogenic hypomorphic variant in a mouse model. Rad51bc.92delT/c.92delT mice exhibited meiotic DNA repair defects due to RAD51 and HSF2BP/BMRE1 accumulation in the chromosome axes leading to a reduction in the number of crossovers. Interestingly, the interaction of RAD51B-c.92delT with RAD51C and with its newly identified interactors RAD51 and HELQ was abrogated or diminished. Repair of mitomycin-C-induced chromosomal aberrations was impaired in RAD51B/Rad51b-c.92delT human and mouse somatic cells in vitro and in explanted mouse bone marrow cells. Accordingly, Rad51b-c.92delT variant reduced replication fork progression of patient-derived lymphoblastoid cell lines and pluripotent reprogramming efficiency of primary mouse embryonic fibroblasts. Finally, Rad51bc.92delT/c.92delT mice displayed increased incidence of pituitary gland hyperplasia. These results provide new mechanistic insights into the role of RAD51B not only in meiosis but in the maintenance of somatic genome stability.202620262022info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10366/169196reponame:GREDOS. Repositorio Institucional de la Universidad de Salamancainstname:Universidad de Salamanca (USAL)InglésMINECO (PID2020-120326RB-I00)Attribution-NonCommercial-NoDerivatives 4.0 Internacionalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:gredos.usal.es:10366/1691962026-06-07T06:28:51Z
dc.title.none.fl_str_mv A truncating variant of RAD51B associated with primary ovarian insufficiency provides insights into its meiotic and somatic functions
title A truncating variant of RAD51B associated with primary ovarian insufficiency provides insights into its meiotic and somatic functions
spellingShingle A truncating variant of RAD51B associated with primary ovarian insufficiency provides insights into its meiotic and somatic functions
Franca, Monica M
Meiosis
POI fertility
DNA repair
Chromosome Aberrations
DNA Repair
Meiosis
Primary Ovarian Insufficiency
Fibroblasts
DNA-Binding Proteins
Humans
Mice
2407 Biología Celular
2411.16 Fisiología de la Reproducción
fibroblastos
meiosis
insuficiencia ovárica primaria
humanos
ratones
proteínas de unión al ADN
aberraciones cromosómicas
reparación del ADN
title_short A truncating variant of RAD51B associated with primary ovarian insufficiency provides insights into its meiotic and somatic functions
title_full A truncating variant of RAD51B associated with primary ovarian insufficiency provides insights into its meiotic and somatic functions
title_fullStr A truncating variant of RAD51B associated with primary ovarian insufficiency provides insights into its meiotic and somatic functions
title_full_unstemmed A truncating variant of RAD51B associated with primary ovarian insufficiency provides insights into its meiotic and somatic functions
title_sort A truncating variant of RAD51B associated with primary ovarian insufficiency provides insights into its meiotic and somatic functions
dc.creator.none.fl_str_mv Franca, Monica M
Condezo, Yazmine B
Elzaiat, Maëva
Felipe-Medina, Natalia
Sánchez Sáez, Fernando
Muñoz, Sergio
Sainz-Urruela, Raquel
Martín-Hervás, M Rosario
García-Valiente, Rodrigo
Sánchez Martín, Manuel Adolfo
Astudillo, Aurora
Mendez, Juan
Llano Cuadra, María Elena
Veitia, Reiner A
Mendonca, Berenice B
Pendás, Alberto M
author Franca, Monica M
author_facet Franca, Monica M
Condezo, Yazmine B
Elzaiat, Maëva
Felipe-Medina, Natalia
Sánchez Sáez, Fernando
Muñoz, Sergio
Sainz-Urruela, Raquel
Martín-Hervás, M Rosario
García-Valiente, Rodrigo
Sánchez Martín, Manuel Adolfo
Astudillo, Aurora
Mendez, Juan
Llano Cuadra, María Elena
Veitia, Reiner A
Mendonca, Berenice B
Pendás, Alberto M
author_role author
author2 Condezo, Yazmine B
Elzaiat, Maëva
Felipe-Medina, Natalia
Sánchez Sáez, Fernando
Muñoz, Sergio
Sainz-Urruela, Raquel
Martín-Hervás, M Rosario
García-Valiente, Rodrigo
Sánchez Martín, Manuel Adolfo
Astudillo, Aurora
Mendez, Juan
Llano Cuadra, María Elena
Veitia, Reiner A
Mendonca, Berenice B
Pendás, Alberto M
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Meiosis
POI fertility
DNA repair
Chromosome Aberrations
DNA Repair
Meiosis
Primary Ovarian Insufficiency
Fibroblasts
DNA-Binding Proteins
Humans
Mice
2407 Biología Celular
2411.16 Fisiología de la Reproducción
fibroblastos
meiosis
insuficiencia ovárica primaria
humanos
ratones
proteínas de unión al ADN
aberraciones cromosómicas
reparación del ADN
topic Meiosis
POI fertility
DNA repair
Chromosome Aberrations
DNA Repair
Meiosis
Primary Ovarian Insufficiency
Fibroblasts
DNA-Binding Proteins
Humans
Mice
2407 Biología Celular
2411.16 Fisiología de la Reproducción
fibroblastos
meiosis
insuficiencia ovárica primaria
humanos
ratones
proteínas de unión al ADN
aberraciones cromosómicas
reparación del ADN
description [EN]Primary ovarian insufficiency (POI) causes female infertility by abolishing normal ovarian function. Although its genetic etiology has been extensively investigated, most POI cases remain unexplained. Using whole-exome sequencing, we identified a homozygous variant in RAD51B -(c.92delT) in two sisters with POI. In vitro studies revealed that this variant leads to translation reinitiation at methionine 64. Here, we show that this is a pathogenic hypomorphic variant in a mouse model. Rad51bc.92delT/c.92delT mice exhibited meiotic DNA repair defects due to RAD51 and HSF2BP/BMRE1 accumulation in the chromosome axes leading to a reduction in the number of crossovers. Interestingly, the interaction of RAD51B-c.92delT with RAD51C and with its newly identified interactors RAD51 and HELQ was abrogated or diminished. Repair of mitomycin-C-induced chromosomal aberrations was impaired in RAD51B/Rad51b-c.92delT human and mouse somatic cells in vitro and in explanted mouse bone marrow cells. Accordingly, Rad51b-c.92delT variant reduced replication fork progression of patient-derived lymphoblastoid cell lines and pluripotent reprogramming efficiency of primary mouse embryonic fibroblasts. Finally, Rad51bc.92delT/c.92delT mice displayed increased incidence of pituitary gland hyperplasia. These results provide new mechanistic insights into the role of RAD51B not only in meiosis but in the maintenance of somatic genome stability.
publishDate 2022
dc.date.none.fl_str_mv 2022
2026
2026
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10366/169196
url http://hdl.handle.net/10366/169196
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv MINECO (PID2020-120326RB-I00)
dc.rights.none.fl_str_mv Attribution-NonCommercial-NoDerivatives 4.0 Internacional
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv Attribution-NonCommercial-NoDerivatives 4.0 Internacional
http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:GREDOS. Repositorio Institucional de la Universidad de Salamanca
instname:Universidad de Salamanca (USAL)
instname_str Universidad de Salamanca (USAL)
reponame_str GREDOS. Repositorio Institucional de la Universidad de Salamanca
collection GREDOS. Repositorio Institucional de la Universidad de Salamanca
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,812429

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