The FANC/BRCA Pathway Releases Replication Blockades by Eliminating DNA Interstrand Cross-Links
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 i...
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MDPI AG
2020-05-01
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Series: | Genes |
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Online Access: | https://www.mdpi.com/2073-4425/11/5/585 |
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author | Xavier Renaudin Filippo Rosselli |
author_facet | Xavier Renaudin Filippo Rosselli |
author_sort | Xavier Renaudin |
collection | DOAJ |
description | 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. |
first_indexed | 2024-03-10T19:36:31Z |
format | Article |
id | doaj.art-510ebfeaf4d544899817fb442f504b85 |
institution | Directory Open Access Journal |
issn | 2073-4425 |
language | English |
last_indexed | 2024-03-10T19:36:31Z |
publishDate | 2020-05-01 |
publisher | MDPI AG |
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series | Genes |
spelling | doaj.art-510ebfeaf4d544899817fb442f504b852023-11-20T01:37:14ZengMDPI AGGenes2073-44252020-05-0111558510.3390/genes11050585The FANC/BRCA Pathway Releases Replication Blockades by Eliminating DNA Interstrand Cross-LinksXavier Renaudin0Filippo Rosselli1CNRS UMR9019, Université Paris-Saclay, Gustave Roussy Institute, 94801 Villejuif, FranceCNRS UMR9019, Université Paris-Saclay, Gustave Roussy Institute, 94801 Villejuif, FranceDNA 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.https://www.mdpi.com/2073-4425/11/5/585FANC/BRCA pathwayinterstrand cross-link (ICL)DNA repairgenomic instability |
spellingShingle | Xavier Renaudin Filippo Rosselli The FANC/BRCA Pathway Releases Replication Blockades by Eliminating DNA Interstrand Cross-Links Genes FANC/BRCA pathway interstrand cross-link (ICL) DNA repair genomic instability |
title | The FANC/BRCA Pathway Releases Replication Blockades by Eliminating DNA Interstrand Cross-Links |
title_full | The FANC/BRCA Pathway Releases Replication Blockades by Eliminating DNA Interstrand Cross-Links |
title_fullStr | The FANC/BRCA Pathway Releases Replication Blockades by Eliminating DNA Interstrand Cross-Links |
title_full_unstemmed | The FANC/BRCA Pathway Releases Replication Blockades by Eliminating DNA Interstrand Cross-Links |
title_short | The FANC/BRCA Pathway Releases Replication Blockades by Eliminating DNA Interstrand Cross-Links |
title_sort | fanc brca pathway releases replication blockades by eliminating dna interstrand cross links |
topic | FANC/BRCA pathway interstrand cross-link (ICL) DNA repair genomic instability |
url | https://www.mdpi.com/2073-4425/11/5/585 |
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