Chromosome Instability in Fanconi Anemia: From Breaks to Phenotypic Consequences

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.

Monoparental disomy in Fanconi anemia

“…Asimismo, la sospecha de AF puede confirmarse por el test de hipersensibilidad frente a agentes capaces de generar entrecruzamientos, como el DEB o MMC, sobre linfocitos purificados de una muestra de sangre periférica (6). No obstante, los grandes avances en biología molecular y secuenciación han permitido identificar las variantes genéticas de interés para mejorar la confirmación diagnóstica (8,9).…”

“…Este fallo de los mecanismos de reparación condiciona una exacerbada sensibilidad de las células de los pacientes a agentes que generen enlaces cruzados en el ADN. Estos agentes pueden ser físicos (radiaciones ionizantes o luz ultravioleta) o químicos (entre los que destacan la mitomicina C[MMC] o el diepoxibutano [DEB])(6). De hecho, el aumento de aberraciones cromosómicas inducidas por la MMC y el DEB a dosis bajas proporciona la base para el test diagnóstico de la AF.…”

Biomarkers of DNA Damage Response Enable Flow Cytometry-Based Diagnostic to Identify Inborn DNA Repair Defects in Primary Immunodeficiencies

“…The Fanconi Anemia (FA) complex consists of at least 22 proteins, many operating in HR, such as BRCA1, BRCA2, and RAD51 [36]. FA-proteins are needed for repair of ICLs, and induction of HR to resolve DNA DSB after ICL resection.…”

“…FA-proteins are needed for repair of ICLs, and induction of HR to resolve DNA DSB after ICL resection. Patients with FA can present with multiple congenital abnormalities, bone marrow failure, endocrine dysfunction, and cancer [36]. Mild immunodeficiency with impaired B and NK cell function has been reported in FA patients [37].…”

In BRCA1 and BRCA2 Breast Cancers, Chromosome Breaks Occur near Herpes Tumor Virus Sequences

“…Mutations that inactivate either the BRCA1 or BRCA2 gene force DNA break repairs into less accurate, errorproducing pathways that do not use a template [1]. Without template guidance during repairs, chromosomes can undergo visible insertions, deletions, and rearrangements because large DNA fragments do not reattach at their original positions [2][3][4]. BRCA1 also participates in the S-phase and G2/M checkpoints [5][6][7], so signals from broken chromosomes become unable to pause cell replication to allow repairs.…”