Aurora A kinase is required for activation of the Fanconi anemia/BRCA pathway upon DNA damage

Min Jeong Chun, Soo Kyung Hwang, Hyoun Geun Kim, Sung Ho Goh, Sunshin Kim, Chang Hun Lee

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Previous studies have linked the DNA damage response to mitotic progression machinery. Mitotic kinases, such as Aurora A kinase and Polo-like kinase, are involved in the phosphorylation of cell cycle regulators in response to DNA damage. Here, we investigated the potential involvement of Aurora A kinase in the activation of the Fanconi anemia (FA)/BRCA pathway, which participates in cellular response to DNA interstrand cross-link lesions (ICL). Initially, we detected interactions between Aurora A kinase and FANCA protein, one of the components of the FA nuclear core complex. Silencing of Aurora A kinase led to inhibition of monoubiquitination of FANCD2 and formation of nuclear foci, the final consequences of FA/BRCA pathway activation upon ICL induction. An in vitro kinase assay revealed that Aurora A kinase phosphorylates S165 of FANCA. Moreover, this phosphorylation event was induced by the treatment with mitomycin C (MMC), an ICL-inducing agent. In cells overexpressing S165A mutant FANCA, monoubiquitination of FANCD2 and nuclear foci formation was impaired and cellular sensitivity to MMC was enhanced. These results suggest that S165 phosphorylation by Aurora A kinase is required for proper activation of the FA/BRCA pathway in response to DNA damage. This study provides evidence supporting the requirement of Aurora A kinase in the activation of the FA/BRCA pathway upon induction of DNA interstrand cross-link lesions. Aurora A kinase has been confirmed to phosphorylate the S165 residue of FANCA protein. We have also presented data suggesting that the S165 residue is important for proper activation of the FA/BRCA pathway.

Original languageEnglish
Pages (from-to)782-790
Number of pages9
JournalFEBS Open Bio
Volume6
Issue number7
DOIs
StatePublished - 1 Jul 2016

Keywords

  • Aurora A kinase
  • DNA interstrand cross-link lesions
  • Fanconi anemia/BRCA pathway

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