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Nucleic Acids Research Advance Access published online on August 6, 2008
Nucleic Acids Research, doi:10.1093/nar/gkn506
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© 2008 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Molecular Biology

A functional genome-wide RNAi screen identifies TAF1 as a regulator for apoptosis in response to genotoxic stress

Junko Kimura, Su Tien Nguyen, Hanshao Liu, Naoe Taira, Yoshio Miki* and Kiyotsugu Yoshida*

Department of Molecular Genetics, Medical Research Institute, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-ku, Tokyo 113-8510, Japan

*To whom correspondence should be addressed. Tel: +81 3 5803 5826; Fax: +81 3 5803 0242; Email: yos.mgen{at}mri.tmd.ac.jp Correspondence may also be addressed to Yoshio Miki. Tel: +81 3 5803 5825; Fax: +81 3 5803 0242; Email: miki.mgen{at}mri.tmd.ac.jp

Received June 18, 2008. Accepted July 22, 2008.

Evasion from apoptotic cell death is a characteristic of cancer; genes that modulate this process may be optimal for therapeutic attack. Identifying key regulators of apoptosis is thus a central goal in cancer therapy. Here, we describe a loss-of-function screen that uses RNA interference libraries to identify genes required for induction of apoptosis. We used a short-hairpin RNA expressing vector with high gene-expression silencing activity that contained fetal brain cDNAs. Survived cells from genotoxic stress were isolated to determine knock-down of molecules that are crucial for induction of apoptosis. We identified TBP-associated factor 1 (TAF1), a gene previously implicated as an essential component of transcription machinery. Depletion of TAF1 was associated with substantial attenuation of apoptosis induced by oxidative as well as genotoxic stress. Microarray analysis further demonstrated that a number of genes were transcriptionally declined in cells silenced for TAF1. Surprisingly, knocking down TAF1 exhibited a marked decrease in p27Kip1 expression, allowing cells resistant from oxidative stress-induced apoptosis. These results suggest that TAF1 regulates apoptosis by controlling p27Kip1 expression. Our system provides a novel approach to identifying candidate genes that modulate apoptosis.


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