Histone lysine methyltransferase SETD8 promotes carcinogenesis by deregulating PCNA expression
Masashi Takawa1, Hyun-Soo Cho, Shinya Hayami
1Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, and National Cancer Center Hospital, Chuo-ku, Tokyo, Japan.
Cancer Research
|May 5, 2012
Summary
Histone lysine methylation is known, but its role in nonhistone proteins was unclear. This study reveals SETD8 methylates PCNA, impacting DNA replication and potentially causing cancer.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Lysine methylation is a key epigenetic regulator for histones.
- The role of lysine methylation in nonhistone proteins remains largely unexplored.
- SETD8, a histone methyltransferase, is implicated in cancer and cell cycle progression.
Purpose of the Study:
- To investigate the role of SETD8 in regulating nonhistone proteins via lysine methylation.
- To determine if proliferating cell nuclear antigen (PCNA) is a target of SETD8-mediated methylation.
- To elucidate the functional consequences of PCNA lysine methylation in DNA replication and cancer.
Main Methods:
- Utilized biochemical assays to demonstrate SETD8-mediated methylation of PCNA at lysine 248.
- Employed gene depletion and site-directed mutagenesis to assess the impact of PCNA methylation.
- Analyzed DNA replication, Okazaki fragment maturation, and DNA damage in response to altered PCNA methylation.
- Correlated SETD8 and PCNA expression in human cancer tissues.
Main Results:
- SETD8 directly methylates PCNA on lysine 248, stabilizing its expression.
- PCNA methylation enhances its interaction with flap endonuclease FEN1.
- Loss of PCNA methylation impairs Okazaki fragment maturation, slows DNA replication, and induces DNA damage.
- Methylated PCNA is elevated in cancer cells, with SETD8 and PCNA expression correlating in tumor samples.
Conclusions:
- This study identifies lysine methylation as a regulatory mechanism for the nonhistone protein PCNA.
- Aberrant lysine methylation of PCNA, mediated by SETD8, contributes to DNA replication defects and may play a role in human carcinogenesis.
- Targeting SETD8-mediated PCNA methylation presents a potential therapeutic strategy for cancer.
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