title: Aurora A kinase is required for activation of the Fanconi anemia/BRCA pathway upon DNA damage.
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.
authors.affiliation: Cancer Cell and Molecular Biology Branch Research Institute National Cancer Center Goyang Gyeonggi Korea.
authors.forename: Min Jeong
authors.initials: MJ
authors.lastname: Chun
authors.affiliation: Cancer Cell and Molecular Biology Branch Research Institute National Cancer Center Goyang Gyeonggi Korea.
authors.forename: Soo Kyung
authors.initials: SK
authors.lastname: Hwang
authors.affiliation: Cancer Cell and Molecular Biology Branch Research Institute National Cancer Center Goyang Gyeonggi Korea.
authors.forename: Hyoun Geun
authors.initials: HG
authors.lastname: Kim
authors.affiliation: Precision Medicine Branch Research Institute National Cancer Center Goyang Gyeonggi Korea.
authors.forename: Sung-Ho
authors.initials: SH
authors.lastname: Goh
authors.affiliation: Precision Medicine Branch Research Institute National Cancer Center Goyang Gyeonggi Korea.
authors.forename: Sunshin
authors.initials: S
authors.lastname: Kim
authors.affiliation: Cancer Cell and Molecular Biology Branch Research Institute National Cancer Center Goyang Gyeonggi Korea.
authors.forename: Chang-Hun
authors.identifier: 0000-0002-4083-2077
authors.initials: CH
authors.lastname: Lee
keywords: Aurora A kinase; DNA interstrand cross‐link lesions; Fanconi anemia/BRCA pathway