FAAP100 is essential for activation of the Fanconi anemia-associated DNA damage response pathway

Chen Ling, Masamichi Ishiai, Abdullah Mahmood Ali, Annette L. Medhurst, Kornelia Neveling, Reinhard Kalb, Zhijiang Yan, Yutong Xue, Anneke B. Oostra, Arleen D. Auerbach, Maureen Hoatlin, Detlev Schindler, Hans Joenje, Johan P. De Winter, Minoru Takata, Amom Ruhikanta Meetei, Weidong Wang

Research output: Contribution to journalArticle

107 Citations (Scopus)

Abstract

The Fanconi anemia (FA) core complex plays a central role in the DNA damage response network involving breast cancer susceptibility gene products, BRCA1 and BRCA2. The complex consists of eight FA proteins, including a ubiquitin ligase (FANCL) and a DNA translocase (FANCM), and is essential for monoubiquitination of FANCD2 in response to DNA damage. Here, we report a novel component of this complex, termed FAAP100, which is essential for the stability of the core complex and directly interacts with FANCB and FANCL to form a stable subcomplex. Formation of this subcomplex protects each component from proteolytic degradation and also allows their coregulation by FANCA and FANCM during nuclear localization. Using siRNA depletion and gene knockout techniques, we show that FAAP100-deficient cells display hallmark features of FA cells, including defective FANCD2 monoubiquitination, hypersensitivity to DNA crosslinking agents, and genomic instability. Our study identifies FAAP100 as a new critical component of the FA-BRCA DNA damage response network.

Original languageEnglish (US)
Pages (from-to)2104-2114
Number of pages11
JournalEMBO Journal
Volume26
Issue number8
DOIs
StatePublished - Apr 18 2007

Fingerprint

Fanconi Anemia
DNA Damage
Chemical activation
DNA
Fanconi Anemia Complementation Group Proteins
Gene Knockout Techniques
Genomic Instability
Neoplasm Genes
Ligases
Ubiquitin
BRCA2 Protein
Small Interfering RNA
BRCA1 Protein
Hypersensitivity
Breast Neoplasms
Crosslinking
Genes
Degradation

Keywords

  • FAAP100
  • FANCB
  • FANCD2
  • FANCL
  • Fanconi anemia

ASJC Scopus subject areas

  • Genetics
  • Cell Biology

Cite this

Ling, C., Ishiai, M., Ali, A. M., Medhurst, A. L., Neveling, K., Kalb, R., ... Wang, W. (2007). FAAP100 is essential for activation of the Fanconi anemia-associated DNA damage response pathway. EMBO Journal, 26(8), 2104-2114. https://doi.org/10.1038/sj.emboj.7601666

FAAP100 is essential for activation of the Fanconi anemia-associated DNA damage response pathway. / Ling, Chen; Ishiai, Masamichi; Ali, Abdullah Mahmood; Medhurst, Annette L.; Neveling, Kornelia; Kalb, Reinhard; Yan, Zhijiang; Xue, Yutong; Oostra, Anneke B.; Auerbach, Arleen D.; Hoatlin, Maureen; Schindler, Detlev; Joenje, Hans; De Winter, Johan P.; Takata, Minoru; Meetei, Amom Ruhikanta; Wang, Weidong.

In: EMBO Journal, Vol. 26, No. 8, 18.04.2007, p. 2104-2114.

Research output: Contribution to journalArticle

Ling, C, Ishiai, M, Ali, AM, Medhurst, AL, Neveling, K, Kalb, R, Yan, Z, Xue, Y, Oostra, AB, Auerbach, AD, Hoatlin, M, Schindler, D, Joenje, H, De Winter, JP, Takata, M, Meetei, AR & Wang, W 2007, 'FAAP100 is essential for activation of the Fanconi anemia-associated DNA damage response pathway', EMBO Journal, vol. 26, no. 8, pp. 2104-2114. https://doi.org/10.1038/sj.emboj.7601666
Ling, Chen ; Ishiai, Masamichi ; Ali, Abdullah Mahmood ; Medhurst, Annette L. ; Neveling, Kornelia ; Kalb, Reinhard ; Yan, Zhijiang ; Xue, Yutong ; Oostra, Anneke B. ; Auerbach, Arleen D. ; Hoatlin, Maureen ; Schindler, Detlev ; Joenje, Hans ; De Winter, Johan P. ; Takata, Minoru ; Meetei, Amom Ruhikanta ; Wang, Weidong. / FAAP100 is essential for activation of the Fanconi anemia-associated DNA damage response pathway. In: EMBO Journal. 2007 ; Vol. 26, No. 8. pp. 2104-2114.
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