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 language | English |
|---|---|
| Pages (from-to) | 3217-3227 |
| Number of pages | 11 |
| Journal | Cancer Research |
| Volume | 72 |
| Issue number | 13 |
| DOIs | |
| Publication status | Published - Jul 1 2012 |
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All Science Journal Classification (ASJC) codes
- Oncology
- Cancer Research
Cite this
Histone lysine methyltransferase setd8 promotes carcinogenesis by deregulating PCNA expression. / Takawa, Masashi; Cho, Hyun Soo; Hayami, Shinya; Toyokawa, Gouji; Kogure, Masaharu; Yamane, Yuka; Iwai, Yukiko; Maejima, Kazuhiro; Ueda, Koji; Masuda, Akiko; Dohmae, Naoshi; Field, Helen I.; Tsunoda, Tatsuhiko; Kobayashi, Takaaki; Akasu, Takayuki; Sugiyama, Masanori; Ohnuma, Shin Ichi; Atomi, Yutaka; Ponder, Bruce A.J.; Nakamura, Yusuke; Hamamoto, Ryuji.
In: Cancer Research, Vol. 72, No. 13, 01.07.2012, p. 3217-3227.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Histone lysine methyltransferase setd8 promotes carcinogenesis by deregulating PCNA expression
AU - Takawa, Masashi
AU - Cho, Hyun Soo
AU - Hayami, Shinya
AU - Toyokawa, Gouji
AU - Kogure, Masaharu
AU - Yamane, Yuka
AU - Iwai, Yukiko
AU - Maejima, Kazuhiro
AU - Ueda, Koji
AU - Masuda, Akiko
AU - Dohmae, Naoshi
AU - Field, Helen I.
AU - Tsunoda, Tatsuhiko
AU - Kobayashi, Takaaki
AU - Akasu, Takayuki
AU - Sugiyama, Masanori
AU - Ohnuma, Shin Ichi
AU - Atomi, Yutaka
AU - Ponder, Bruce A.J.
AU - Nakamura, Yusuke
AU - Hamamoto, Ryuji
PY - 2012/7/1
Y1 - 2012/7/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84863579070&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84863579070&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-11-3701
DO - 10.1158/0008-5472.CAN-11-3701
M3 - Article
C2 - 22556262
AN - SCOPUS:84863579070
VL - 72
SP - 3217
EP - 3227
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 13
ER -