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J. Biol. Chem., Vol. 279, Issue 9, 8190-8195, February 27, 2004

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A Novel Hydrogen Peroxide-induced Phosphorylation and Ubiquitination Pathway Leading to RNA Polymerase II Proteolysis^*

Naoto Inukai, Yuki Yamaguchi, Isao Kuraoka¶, Tomoko Yamada, Sachiko Kamijo, Junko Kato, Kiyoji Tanaka¶, and Hiroshi Handa||

From the Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology and PRESTO, Japan Science and Technology Agency, Yokohama 226-8501, Japan and the ^¶Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka 565-0871, Japan

DNA damage-induced ubiquitination of the largest subunit of RNA polymerase II, Rpb1, has been implicated in transcription-coupled repair for years. The studies so far, however, have been limited to the use of bulky helix-distorting DNA damages caused by UV light and cisplatin, which are corrected by the nucleotide excision repair pathway. Non-bulky, non-helix-distorting damages are caused at high frequency by reactive oxygen species in cells and corrected by the base excision repair pathway. Contrary to a classic view, we recently found that the second type of DNA lesions also causes RNA polymerase II stalling in vitro. In this paper, we show that hydrogen peroxide (H₂O₂) causes significant ubiquitination and proteasomal degradation of Rpb1 by mechanisms that are distinct from those employed after UV irradiation. UV irradiation and H₂O₂ treatment cause characteristic changes in protein kinases phosphorylating the carboxyl-terminal domain at Ser-2 and -5. The H₂O₂-induced ubiquitination is likely dependent on unusual Ser-5 phosphorylation by ERK1/2. Moreover, the H₂O₂-induced ubiquitination occurs on transcriptionally engaged polymerases without the help of Cockayne syndrome A and B proteins and von Hippel-Lindau tumor suppressor proteins, which are all required for the UV-induced ubiquitination. These results suggest that stalled polymerases are recognized and ubiquitinated differentially depending on the types of DNA lesions. Our findings may have general implications in the basic mechanism of transcription-coupled nucleotide excision repair and base excision repair.

Received for publication, October 17, 2003 , and in revised form, December 1, 2003.

^* This work was supported by a grant from the 21st Century COE Program, a grant-in-aid for scientific research from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and by a grant for Research and Development Projects in Cooperation with Academic Institutions from the New Energy and Industrial Technology Development Organization. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, 4259 Nagatsuta, Yokohama 226-8501, Japan. Tel.: 81-45-924-5872; Fax: 81-45-924-5145; E-mail: hhanda{at}bio.titech.ac.jp.

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