title: Hypoxic stress facilitates acute activation and chronic downregulation of fanconi anemia proteins.
abstract: Hypoxia induces genomic instability through replication stress and dysregulation of vital DNA repair pathways. The Fanconi anemia (FA) proteins, FANCD2 and FANCI, are key members of a DNA repair pathway that responds to replicative stress, suggesting that they undergo regulation by hypoxic conditions. Here acute hypoxic stress activates the FA pathway via ubiquitination of FANCD2 and FANCI in an ATR-dependent manner. In addition, the presence of an intact FA pathway is required for preventing hypoxia-induced DNA damage measurable by the comet assay, limiting the accumulation of γH2AX (a marker of DNA damage or stalled replication), and protecting cells from hypoxia-induced apoptosis. Furthermore, prolonged hypoxia induces transcriptional repression of FANCD2 in a manner analogous to the hypoxic downregulation of BRCA1 and RAD51. Thus, hypoxia-induced FA pathway activation plays a key role in maintaining genome integrity and cell survival, while FA protein downregulation with prolonged hypoxia contributes to genomic instability.
  
  
  CONCLUSIONS
  This work highlights the critical role of the FA pathway in response to hypoxic stress and identifies the pathway as a therapeutic target under hypoxic conditions.
authors.affiliation: Authors' Affiliations: Departments of Therapeutic Radiology, Experimental Pathology, and.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Scanlon
authors.affiliation: Authors' Affiliations: Departments of Therapeutic Radiology, Genetics, Yale University School of Medicine, New Haven, Connecticut peter.glazer@yale.edu.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Glazer
mesh_terms: D015687:Cell Hypoxia / Q000235:genetics / Q000502:physiology; D004249:DNA Damage; D004260:DNA Repair; D004261:DNA Replication; D015536:Down-Regulation; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000235:genetics / Q000378:metabolism; D051856:Fanconi Anemia Complementation Group Proteins / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D061986:MCF-7 Cells; D054875:Ubiquitination
chemical_list: C499905:FANCD2 protein, human; C519921:FANCI protein, human; D052236:Fanconi Anemia Complementation Group D2 Protein; D051856:Fanconi Anemia Complementation Group Proteins