A novel interplay between the Fanconi anemia core complex and ATR-ATRIP kinase during DNA cross-link repair

Junya Tomida, Akiko Itaya, Tomoko Shigechi, Junya Unno, Emi Uchida, Masae Ikura, Yuji Masuda, Shun Matsuda, Jun Adachi, Masahiko Kobayashi, Amom Ruhikanta Meetei, Yoshihiko Maehara, Ken Ichi Yamamoto, Kenji Kamiya, Akira Matsuura, Tomonari Matsuda, Tsuyoshi Ikura, Masamichi Ishiai, Minoru Takata

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

When DNA replication is stalled at sites of DNA damage, a cascade of responses is activated in the cell to halt cell cycle progression and promote DNA repair. A pathway initiated by the kinase Ataxia teleangiectasia and Rad3 related (ATR) and its partner ATR interacting protein (ATRIP) plays an important role in this response. The Fanconi anemia (FA) pathway is also activated following genomic stress, and defects in this pathway cause a cancer-prone hematologic disorder in humans. Little is known about how these two pathways are coordinated. We report here that following cellular exposure to DNA cross-linking damage, the FA core complex enhances binding and localization of ATRIP within damaged chromatin. In cells lacking the core complex, ATR-mediated phosphorylation of two functional response targets, ATRIP and FANCI, is defective. We also provide evidence that the canonical ATR activation pathway involving RAD17 and TOPBP1 is largely dispensable for the FA pathway activation. Indeed DT40 mutant cells lacking both RAD17 and FANCD2 were synergistically more sensitive to cisplatin compared with either single mutant. Collectively, these data reveal new aspects of the interplay between regulation of ATR-ATRIP kinase and activation of the FA pathway.

Original languageEnglish
Pages (from-to)6930-6941
Number of pages12
JournalNucleic acids research
Volume41
Issue number14
DOIs
Publication statusPublished - Aug 2013
Externally publishedYes

ASJC Scopus subject areas

  • Genetics

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    Tomida, J., Itaya, A., Shigechi, T., Unno, J., Uchida, E., Ikura, M., Masuda, Y., Matsuda, S., Adachi, J., Kobayashi, M., Meetei, A. R., Maehara, Y., Yamamoto, K. I., Kamiya, K., Matsuura, A., Matsuda, T., Ikura, T., Ishiai, M., & Takata, M. (2013). A novel interplay between the Fanconi anemia core complex and ATR-ATRIP kinase during DNA cross-link repair. Nucleic acids research, 41(14), 6930-6941. https://doi.org/10.1093/nar/gkt467