2020
DOI: 10.1002/em.22358
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Fanconi anemia and the underlying causes of genomic instability

Abstract: Fanconi anemia (FA) is a rare genetic disorder, characterized by birth defects, progressive bone marrow failure, and a predisposition to cancer. This devastating disease is caused by germline mutations in any one of the 22 known FA genes, where the gene products are primarily responsible for the resolution of DNA interstrand cross‐links (ICLs), a type of DNA damage generally formed by cytotoxic chemotherapeutic agents. However, the identity of endogenous mutagens that generate DNA ICLs remains largely elusive.… Show more

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Cited by 29 publications
(37 citation statements)
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“…Hereafter, we discuss how replication stress can impact the mitotic process and result in both structural and numerical CIN, acting to restrain proliferation or promote genetic diversification during tumor evolution. This connection between replication stress and CIN may be key to understanding the pathogenetic mechanisms involved in chromosomal instability and cancer-prone syndromes, such as ataxia telangiectasia (AT), familial cutaneous telangiectasia and cancer syndrome, Seckel syndrome, Bloom syndrome or Fanconi anemia, as well as to understanding the role of CIN in cancer [38][39][40][41][42][43].…”
Section: Causes Of Replication Stress and Its Role In Chromosomal Insmentioning
confidence: 99%
“…Hereafter, we discuss how replication stress can impact the mitotic process and result in both structural and numerical CIN, acting to restrain proliferation or promote genetic diversification during tumor evolution. This connection between replication stress and CIN may be key to understanding the pathogenetic mechanisms involved in chromosomal instability and cancer-prone syndromes, such as ataxia telangiectasia (AT), familial cutaneous telangiectasia and cancer syndrome, Seckel syndrome, Bloom syndrome or Fanconi anemia, as well as to understanding the role of CIN in cancer [38][39][40][41][42][43].…”
Section: Causes Of Replication Stress and Its Role In Chromosomal Insmentioning
confidence: 99%
“…The cycle finishes with the deubiquitination and unloading of the ID2 complex by USP1-UAF1, and the removal of the ICL-adduct by the NER (nucleotide excision repair) pathway. [9,12,[22][23][24]…”
Section: Involvement Of Fa/brca Pathway In Dna Repairmentioning
confidence: 99%
“…When the synapsis has been stabilized, dissociation of FANCR/RAD51 is required to promote DNA synthesis. A displacement-loop (D-loop) is then formed allowing the engagement of the DNA polymerase δ (Pol δ) [14,23,27,30] to incorporate nucleotides and synthesize new DNA. The DNA heteroduplex leads to the formation of Holliday junctions, which are resolved by helicases and endonucleases.…”
Section: Homologous Recombinationmentioning
confidence: 99%
“…Alternatively POLQ can direct DNA synthesis to add nucleotides to make DNA ends compatible, this end processing generates in situ deletions and duplications. In addition, if this pathway is active during S/G2 and several DSBs coincide in time and space, gross chromosomal aberrations are formed, because, like NHEJ, they do not require long stretches of homology to ligate the DNA ends [21,23].…”
Section: Repair Of Double Strand Breaksmentioning
confidence: 99%
“…When the synapsis is stabilized, the dissociation of FANCR/RAD51 promotes DNA synthesis, a displacement-loop (D-loop) is formed that engages the DNA polymerase δ (Pol δ) [12,21,23,25] to incorporate nucleotides and synthesize new DNA for completing the homologous recombination process. The heteroduplex DNA, forms Holliday junctions, which are resolved by helicases and endonucleases that depending on its dissolution or resolution, conduces to restore the original sequence by gene conversion, or sister chromatid exchange, avoiding chromosomal translocations, as expected by an error-free repair [26,27] (Figure 2).…”
Section: Homologous Recombinationmentioning
confidence: 99%