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 E. Hoatlin; Detlev Schindler; Hans Joenje; Johan P. De Winter; Minoru Takata; Amom Ruhikanta Meetei; Weidong Wang

doi:10.1038/sj.emboj.7601666

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 E. Hoatlin, Detlev Schindler, Hans Joenje, Johan P. De Winter, Minoru Takata, Amom Ruhikanta Meetei, Weidong Wang

Biochemistry & Molecular Biology

Research output: Contribution to journal › Article › peer-review

122 Scopus citations

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 language	English (US)
Pages (from-to)	2104-2114
Number of pages	11
Journal	EMBO Journal
Volume	26
Issue number	8
DOIs	https://doi.org/10.1038/sj.emboj.7601666
State	Published - Apr 18 2007

Keywords

FAAP100
FANCB
FANCD2
FANCL
Fanconi anemia

ASJC Scopus subject areas

General Neuroscience
Molecular Biology
General Biochemistry, Genetics and Molecular Biology
General Immunology and Microbiology

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Ling, C., Ishiai, M., Ali, A. M., Medhurst, A. L., Neveling, K., Kalb, R., Yan, Z., Xue, Y., Oostra, A. B., Auerbach, A. D., Hoatlin, M. E., Schindler, D., Joenje, H., De Winter, J. P., Takata, M., Meetei, A. 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

Ling, C, Ishiai, M, Ali, AM, Medhurst, AL, Neveling, K, Kalb, R, Yan, Z, Xue, Y, Oostra, AB, Auerbach, AD, Hoatlin, ME, 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

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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.",

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AU - Ishiai, Masamichi

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AU - Neveling, Kornelia

AU - Kalb, Reinhard

AU - Yan, Zhijiang

AU - Xue, Yutong

AU - Oostra, Anneke B.

AU - Auerbach, Arleen D.

AU - Hoatlin, Maureen E.

AU - Schindler, Detlev

AU - Joenje, Hans

AU - De Winter, Johan P.

AU - Takata, Minoru

AU - Meetei, Amom Ruhikanta

AU - Wang, Weidong

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N2 - 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.

AB - 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.

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KW - Fanconi anemia

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

Abstract

Keywords

ASJC Scopus subject areas

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