Abstract
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.
Highlights
Fanconi anemia (FA) is a rare disease with an incidence of 1–5 per million of births and is the most commonly inherited bone marrow failure syndrome [1]
An interesting observation made by Kao et al when analyzing DNA repair pathways in different skin cancers is that the Fanconi anemia/breast cancer (FA/BRCA) pathway may be contributing to melanomagenesis, since genes from this pathway were found to be upregulated in melanoma tumors [122]
The FA/BRCA pathway coordinates the repair of interstrand crosslinks (ICLs) through the error-free DNA repair mechanism known as Homologous recombination (HR)
Summary
Fanconi anemia (FA) is a rare disease with an incidence of 1–5 per million of births and is the most commonly inherited bone marrow failure syndrome [1]. ICLs of exogenous origins are more difficult to assess since for all the agents with the capacity to induce them, only a small fraction (typically 1–5%) will be ICLs, while the majority of the induced DNA damage will be monoadducts or intrastrand crosslinks [5] Most of this damage is successfully repaired via the FA/BRCA pathway. Failure of the FA/BRCA pathway has consequences at various levels of complexity: (1) at the chromosomal level by the presence of numerical and structural chromosomal instability; (2) at the cellular level resulting in increased cell death, alteration of the cell cycle, high sensitivity to oxidative damage and to DNA cross-linking agents, both exogenous such as chemotherapeutic drugs, e.g., cis-platinum, mitomycin C or diepoxybutane, as well as endogenous aldehydes, a product of cell metabolic activities [6,7]; and (3) at the clinical level, where patients with FA present three main features: developmental abnormalities, bone marrow failure and an increased risk of cancer [8]. We present mechanisms responsible for chromosome aberrations, examine the cellular response to DNA damage and discuss possible pathophysiological processes involved in the clinical consequences of DNA damage accumulation
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