Chromosome Instability in Fanconi Anemia: From Breaks to Phenotypic Consequences

Genes (Basel). 2020 Dec 21;11(12):1528. doi: 10.3390/genes11121528.


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.

Keywords: FA pathway; MYC; TGFβ pathway; bone marrow failure; cancer; chromosomal instability; infertility; p53; physical abnormalities; radial figures.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Aging / genetics
  • BRCA1 Protein / physiology
  • BRCA2 Protein / physiology
  • Bone Marrow Failure Disorders / etiology
  • Cell Cycle
  • Chromatids / ultrastructure
  • Chromosomal Instability*
  • Chromosome Aberrations
  • Chromosomes, Human / ultrastructure
  • DNA Breaks, Double-Stranded
  • DNA End-Joining Repair
  • DNA Repair*
  • Fanconi Anemia / complications
  • Fanconi Anemia / diagnosis
  • Fanconi Anemia / genetics*
  • Fanconi Anemia Complementation Group C Protein / deficiency
  • Fanconi Anemia Complementation Group C Protein / genetics
  • Fanconi Anemia Complementation Group C Protein / physiology
  • Humans
  • Infertility / genetics
  • Neoplastic Syndromes, Hereditary / genetics
  • Phenotype
  • Protein Processing, Post-Translational
  • Ubiquitination


  • BRCA1 Protein
  • BRCA1 protein, human
  • BRCA2 Protein
  • BRCA2 protein, human
  • FANCC protein, human
  • Fanconi Anemia Complementation Group C Protein