题名：FAAP100 is essential for activation of the Fanconi anemia-associated DNA damage response pathway.
作者：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.
来源：EMBO J[IF=10.053]. 2007 Mar 29; [Epub ahead of print]
摘要： Chen Ling1, 9, Masamichi Ishiai2, 9, Abdullah Mahmood Ali3, Annette L Medhurst4, Kornelia Neveling5, Reinhard Kalb5, Zhijiang Yan1, Yutong Xue1, Anneke B Oostra4, Arleen D Auerbach6, Maureen E Hoatlin7, Detlev Schindler5, Hans Joenje4, Johan P de Winter4, Minoru Takata2, 8, Amom Ruhikanta Meetei1, 3 and Weidong Wang1
1 Laboratory of Genetics, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA
2 Department of Immunology and Molecular Genetics, Kawasaki Medical School, Kurashiki, Okayama, Japan
3 Division of Experimental Hematology, Cincinnati Children s Hospital Research Foundation and University of Cincinnati College of Medicine, Cincinnati, OH, USA
4 Department of Clinical Genetics, VU Medical Center, Amsterdam, The Netherlands
5 Department of Human Genetics, University of Wurzburg, Wurzburg, Germany
6 Laboratory of Human Genetics and Hematology, The Rockefeller University, New York, NY, USA
7 Department of Biochemistry and Molecular Biology, Oregon Health & Science University, Portland, OR, USA
8 Department of Human Genetics, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
To whom correspondence should be addressed
Weidong Wang, Laboratory of Genetics, National Institute on Aging, NIH, 333 Cassell Drive, TRIAD Center Room 3000, Baltimore, MD 21224, USA. Tel.: +1 410 558 8334; Fax: +1 410 558 8331; E-mail: email@example.com Amom Ruhikanta Meetei, Division of Experimental Hematology, Cincinnati Children s Hospital Research Foundation and University of Cincinnati College of Medicine, 3333 Burnet Avenue, Cincinnati, OH 45229, USA. Tel.: +1 513 636 1768; Fax: +1 513 636 3768; E-mail: Ruhikanta.Meetei@cchmc.org
9 These authors contributed equally to this work
Received 23 October 2006; Accepted 6 March 2007; Published online 29 March 2007.
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.
Keywords: FAAP100, FANCB, FANCD2, FANCL, Fanconi an