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Chromosome Instability in Fanconi Anemia: From Breaks to Phenotypic Consequences

Fanconi anemia (FA), a chromosomal instability syndrome, is caused by inherited pathogenic variants in any of 22 FANC genes, which cooperate in the FA/BRCA pathway. This pathway regulates the repair of DNA interstrand crosslinks (ICLs) through homologous recombination. In FA proper repair of ICLs is...

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Autores principales: García-de-Teresa, Benilde, Rodríguez, Alfredo, Frias, Sara
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7767525/
https://www.ncbi.nlm.nih.gov/pubmed/33371494
http://dx.doi.org/10.3390/genes11121528
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author García-de-Teresa, Benilde
Rodríguez, Alfredo
Frias, Sara
author_facet García-de-Teresa, Benilde
Rodríguez, Alfredo
Frias, Sara
author_sort García-de-Teresa, Benilde
collection PubMed
description Fanconi anemia (FA), a chromosomal instability syndrome, is caused by inherited pathogenic variants in any of 22 FANC genes, which cooperate in the FA/BRCA pathway. This pathway regulates the repair of DNA interstrand crosslinks (ICLs) through homologous recombination. In FA proper repair of ICLs is impaired and accumulation of toxic DNA double strand breaks occurs. To repair this type of DNA damage, FA cells activate alternative error-prone DNA repair pathways, which may lead to the formation of gross structural chromosome aberrations of which radial figures are the hallmark of FA, and their segregation during cell division are the origin of subsequent aberrations such as translocations, dicentrics and acentric fragments. The deficiency in DNA repair has pleiotropic consequences in the phenotype of patients with FA, including developmental alterations, bone marrow failure and an extreme risk to develop cancer. The mechanisms leading to the physical abnormalities during embryonic development have not been clearly elucidated, however FA has features of premature aging with chronic inflammation mediated by pro-inflammatory cytokines, which results in tissue attrition, selection of malignant clones and cancer onset. Moreover, chromosomal instability and cell death are not exclusive of the somatic compartment, they also affect germinal cells, as evidenced by the infertility observed in patients with FA.
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spelling pubmed-77675252020-12-28 Chromosome Instability in Fanconi Anemia: From Breaks to Phenotypic Consequences García-de-Teresa, Benilde Rodríguez, Alfredo Frias, Sara Genes (Basel) Review Fanconi anemia (FA), a chromosomal instability syndrome, is caused by inherited pathogenic variants in any of 22 FANC genes, which cooperate in the FA/BRCA pathway. This pathway regulates the repair of DNA interstrand crosslinks (ICLs) through homologous recombination. In FA proper repair of ICLs is impaired and accumulation of toxic DNA double strand breaks occurs. To repair this type of DNA damage, FA cells activate alternative error-prone DNA repair pathways, which may lead to the formation of gross structural chromosome aberrations of which radial figures are the hallmark of FA, and their segregation during cell division are the origin of subsequent aberrations such as translocations, dicentrics and acentric fragments. The deficiency in DNA repair has pleiotropic consequences in the phenotype of patients with FA, including developmental alterations, bone marrow failure and an extreme risk to develop cancer. The mechanisms leading to the physical abnormalities during embryonic development have not been clearly elucidated, however FA has features of premature aging with chronic inflammation mediated by pro-inflammatory cytokines, which results in tissue attrition, selection of malignant clones and cancer onset. Moreover, chromosomal instability and cell death are not exclusive of the somatic compartment, they also affect germinal cells, as evidenced by the infertility observed in patients with FA. MDPI 2020-12-21 /pmc/articles/PMC7767525/ /pubmed/33371494 http://dx.doi.org/10.3390/genes11121528 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
García-de-Teresa, Benilde
Rodríguez, Alfredo
Frias, Sara
Chromosome Instability in Fanconi Anemia: From Breaks to Phenotypic Consequences
title Chromosome Instability in Fanconi Anemia: From Breaks to Phenotypic Consequences
title_full Chromosome Instability in Fanconi Anemia: From Breaks to Phenotypic Consequences
title_fullStr Chromosome Instability in Fanconi Anemia: From Breaks to Phenotypic Consequences
title_full_unstemmed Chromosome Instability in Fanconi Anemia: From Breaks to Phenotypic Consequences
title_short Chromosome Instability in Fanconi Anemia: From Breaks to Phenotypic Consequences
title_sort chromosome instability in fanconi anemia: from breaks to phenotypic consequences
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7767525/
https://www.ncbi.nlm.nih.gov/pubmed/33371494
http://dx.doi.org/10.3390/genes11121528
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