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

Min Jeong Chun1, Soo Kyung Hwang1, Hyoun Geun Kim1

  • 1Cancer Cell and Molecular Biology Branch Research Institute National Cancer Center Goyang Gyeonggi Korea.

FEBS Open Bio
|July 12, 2016
PubMed

Insights

Aurora A kinase phosphorylates FANCA at S165, a crucial step for activating the Fanconi anemia (FA)/BRCA pathway. This DNA damage response mechanism is vital for repairing interstrand cross-link lesions.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Genetics

Background:

  • The DNA damage response (DDR) is intricately linked to cell cycle regulation and mitotic progression.
  • Mitotic kinases, including Aurora A kinase, play roles in cellular responses to DNA damage by phosphorylating key regulators.

Purpose of the Study:

  • To investigate the role of Aurora A kinase in the activation of the Fanconi anemia (FA)/BRCA pathway.
  • To determine if Aurora A kinase directly phosphorylates components of the FA/BRCA pathway.

Main Methods:

  • Co-immunoprecipitation to detect protein interactions.
  • siRNA-mediated knockdown of Aurora A kinase.
  • In vitro kinase assays.
  • Analysis of FANCD2 monoubiquitination and nuclear foci formation.
  • Site-directed mutagenesis (S165A) and analysis of cellular sensitivity to mitomycin C (MMC).

Main Results:

  • Aurora A kinase interacts with FANCA, a core component of the FA pathway.
  • Silencing Aurora A kinase inhibits FANCD2 monoubiquitination and nuclear foci formation, key markers of FA pathway activation.
  • Aurora A kinase directly phosphorylates FANCA at serine 165 (S165) in vitro.
  • MMC treatment induces S165 phosphorylation of FANCA.
  • Cells expressing a non-phosphorylatable S165A FANCA mutant show impaired FANCD2 monoubiquitination, reduced foci formation, and increased sensitivity to MMC.

Conclusions:

  • Aurora A kinase-mediated phosphorylation of FANCA at S165 is essential for the proper activation of the FA/BRCA pathway.
  • This phosphorylation event is a critical step in the cellular response to DNA interstrand cross-link lesions (ICLs).
  • Aurora A kinase represents a potential therapeutic target for enhancing DNA repair inhibition in cancer treatment.
Keywords:
Aurora A kinaseDNA interstrand cross‐link lesionsFanconi anemia/BRCA pathway

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