Preprint Review Version 2 Preserved in Portico This version is not peer-reviewed

Chromosome Instability in Fanconi Anemia: From Breaks to Phenotypic Consequences

Version 1 : Received: 19 November 2020 / Approved: 23 November 2020 / Online: 23 November 2020 (08:51:42 CET)
Version 2 : Received: 21 December 2020 / Approved: 22 December 2020 / Online: 22 December 2020 (10:58:20 CET)

A peer-reviewed article of this Preprint also exists.

García-de-Teresa, B.; Rodríguez, A.; Frias, S. Chromosome Instability in Fanconi Anemia: From Breaks to Phenotypic Consequences. Genes 2020, 11, 1528. García-de-Teresa, B.; Rodríguez, A.; Frias, S. Chromosome Instability in Fanconi Anemia: From Breaks to Phenotypic Consequences. Genes 2020, 11, 1528.

Journal reference: Genes 2020, 11, 1528
DOI: 10.3390/genes11121528

Abstract

Abstract: Fanconi anemia (FA), a chromosomal instability syndrome, is caused by inherited pathogenic variants in any of 22 FANC genes, that 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. In order to repair this type of DNA damage, FA cells activate alternative error-prone DNA repair pathways, that 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 like 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, that results in tissue attrition, selection of malignant clones and cancer onset. Moreover, the effect of the FA/BRCA pathway in germinal cells, evidenced by infertility in patients with FA attests of chromosomal instability and cell death also occurring in the germinal compartment.

Subject Areas

Chromosomal instability; FA pathway; Radial figures; TGF pathway; MYC; p53; Bone marrow failure; cancer; physical abnormalities; infertility.

Comments (1)

Comment 1
Received: 22 December 2020
Commenter: Sara Frias
Commenter's Conflict of Interests: Author
Comment: The manuscript has been modified, the title was changed from "Causes and Consequences of Chromosomal Instability in Fanconi Anemia. Alterations at the Cellular and Organism Level" to "Chromosome instability in Fanconi anemia: from breaks to phenotypic consequences"
A new section was added:  Fanconi anemia proteins beyond ICL repair
And in general, figures and text were improved.
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