Preprint Review Version 1 Preserved in Portico This version is not peer-reviewed

Causes and Consequences of Chromosomal Instability in Fanconi Anemia. Alterations at the Cellular and Organism Level

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 chromosome 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 epitome and 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.

Keywords

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

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