title: Histone lysine methyltransferase SETD8 promotes carcinogenesis by deregulating PCNA expression.
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.
authors.affiliation: Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, and National Cancer Center Hospital, Chuo-ku, Tokyo, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Takawa
authors.forename: Hyun-Soo
authors.initials: HS
authors.lastname: Cho
authors.forename: Shinya
authors.initials: S
authors.lastname: Hayami
authors.forename: Gouji
authors.initials: G
authors.lastname: Toyokawa
authors.forename: Masaharu
authors.initials: M
authors.lastname: Kogure
authors.forename: Yuka
authors.initials: Y
authors.lastname: Yamane
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Iwai
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Maejima
authors.forename: Koji
authors.initials: K
authors.lastname: Ueda
authors.forename: Akiko
authors.initials: A
authors.lastname: Masuda
authors.forename: Naoshi
authors.initials: N
authors.lastname: Dohmae
authors.forename: Helen I
authors.initials: HI
authors.lastname: Field
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Tsunoda
authors.forename: Takaaki
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Takayuki
authors.initials: T
authors.lastname: Akasu
authors.forename: Masanori
authors.initials: M
authors.lastname: Sugiyama
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Ohnuma
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Atomi
authors.forename: Bruce A J
authors.initials: BA
authors.lastname: Ponder
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Ryuji
authors.initials: R
authors.lastname: Hamamoto
mesh_terms: D000368:Aged; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D004249:DNA Damage; D004261:DNA Replication; D005260:Female; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008297:Male; D008745:Methylation; D008875:Middle Aged; D018809:Proliferating Cell Nuclear Antigen / Q000737:chemistry / Q000378:metabolism*; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D018809:Proliferating Cell Nuclear Antigen; D034741:RNA, Small Interfering; D011495:Histone-Lysine N-Methyltransferase; C470730:KMT5A protein, human; D008239:Lysine