Histone lysine methyltransferase setd8 promotes carcinogenesis by deregulating PCNA expression

Masashi Takawa, Hyun Soo Cho, Shinya Hayami, Gouji Toyokawa, Masaharu Kogure, Yuka Yamane, Yukiko Iwai, Kazuhiro Maejima, Koji Ueda, Akiko Masuda, Naoshi Dohmae, Helen I. Field, Tatsuhiko Tsunoda, Takaaki Kobayashi, Takayuki Akasu, Masanori Sugiyama, Shin Ichi Ohnuma, Yutaka Atomi, Bruce A.J. Ponder, Yusuke NakamuraRyuji Hamamoto

Research output: Contribution to journalArticle

121 Citations (Scopus)

Abstract

Although the physiologic significance of lysine methylation of histones is well known, whether lysine methylation plays a role in the regulation of nonhistone proteins has not yet been examined. The histone lysine methyltransferase SETD8 is overexpressed in various types of cancer and seems to play a crucial role in S-phase progression. Here, we show that SETD8 regulates the function of proliferating cell nuclear antigen (PCNA) protein through lysine methylation. We found that SETD8 methylated PCNA on lysine 248, and either depletion of SETD8 or substitution of lysine 248 destabilized PCNA expression. Mechanistically, lysine methylation significantly enhanced the interaction between PCNA and the flap endonuclease FEN1. Loss of PCNA methylation retarded the maturation of Okazaki fragments, slowed DNA replication, and induced DNA damage, and cells expressing a methylation-inactive PCNA mutant were more susceptible to DNA damage. An increase of methylated PCNA was found in cancer cells, and the expression levels of SETD8 and PCNA were correlated in cancer tissue samples. Together, our findings reveal a function for lysine methylation on a nonhistone protein and suggest that aberrant lysine methylation of PCNA may play a role in human carcinogenesis.

Original languageEnglish
Pages (from-to)3217-3227
Number of pages11
JournalCancer Research
Volume72
Issue number13
DOIs
Publication statusPublished - Jul 1 2012

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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    Takawa, M., Cho, H. S., Hayami, S., Toyokawa, G., Kogure, M., Yamane, Y., Iwai, Y., Maejima, K., Ueda, K., Masuda, A., Dohmae, N., Field, H. I., Tsunoda, T., Kobayashi, T., Akasu, T., Sugiyama, M., Ohnuma, S. I., Atomi, Y., Ponder, B. A. J., ... Hamamoto, R. (2012). Histone lysine methyltransferase setd8 promotes carcinogenesis by deregulating PCNA expression. Cancer Research, 72(13), 3217-3227. https://doi.org/10.1158/0008-5472.CAN-11-3701