The FANC/BRCA Pathway Releases Replication Blockades by Eliminating DNA Interstrand Cross-Links

Genes (Basel). 2020 May 25;11(5):585. doi: 10.3390/genes11050585.


DNA interstrand cross-links (ICLs) represent a major barrier blocking DNA replication fork progression. ICL accumulation results in growth arrest and cell death-particularly in cell populations undergoing high replicative activity, such as cancer and leukemic cells. For this reason, agents able to induce DNA ICLs are widely used as chemotherapeutic drugs. However, ICLs are also generated in cells as byproducts of normal metabolic activities. Therefore, every cell must be capable of rescuing lCL-stalled replication forks while maintaining the genetic stability of the daughter cells in order to survive, replicate DNA and segregate chromosomes at mitosis. Inactivation of the Fanconi anemia/breast cancer-associated (FANC/BRCA) pathway by inherited mutations leads to Fanconi anemia (FA), a rare developmental, cancer-predisposing and chromosome-fragility syndrome. FANC/BRCA is the key hub for a complex and wide network of proteins that-upon rescuing ICL-stalled DNA replication forks-allows cell survival. Understanding how cells cope with ICLs is mandatory to ameliorate ICL-based anticancer therapies and provide the molecular basis to prevent or bypass cancer drug resistance. Here, we review our state-of-the-art understanding of the mechanisms involved in ICL resolution during DNA synthesis, with a major focus on how the FANC/BRCA pathway ensures DNA strand opening and prevents genomic instability.

Keywords: DNA repair; FANC/BRCA pathway; genomic instability; interstrand cross-link (ICL).

Publication types

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

MeSH terms

  • Antineoplastic Agents / adverse effects
  • BRCA1 Protein / genetics*
  • BRCA2 Protein / genetics*
  • DNA Repair / genetics*
  • Drug Resistance, Neoplasm / drug effects
  • Fanconi Anemia / chemically induced
  • Fanconi Anemia / genetics
  • Fanconi Anemia / pathology
  • Fanconi Anemia Complementation Group A Protein / genetics*
  • Genomic Instability / drug effects*
  • Humans
  • Neoplasms / drug therapy
  • Neoplasms / genetics
  • Signal Transduction / drug effects


  • Antineoplastic Agents
  • BRCA1 Protein
  • BRCA1 protein, human
  • BRCA2 Protein
  • BRCA2 protein, human
  • FANCA protein, human
  • Fanconi Anemia Complementation Group A Protein