Histone Lysine Methyltransferase SETD8 Promotes Carcinogenesis by Deregulating PCNA Expression
Histone Lysine Methyltransferase SETD8 Promotes Carcinogenesis by Deregulating PCNA Expression
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DOI：
10.1158/0008-5472.can-11-3701
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发表时间：
2012-07-01
期刊：
影响因子：
11.2
通讯作者：
Hamamoto, Ryuji
中科院分区：
文献类型：
--
作者：
Takawa, Masashi;Cho, Hyun-Soo;Hamamoto, Ryuji
虽然组蛋白赖氨酸甲基化的生理意义是众所周知的，但赖氨酸甲基化是否在非组蛋白的调节中起作用还没有被研究。组蛋白赖氨酸甲基转移酶SETD 8在各种类型的癌症中过表达，似乎在S期进展中起着至关重要的作用。在这里，我们表明，SETD 8调节增殖细胞核抗原（PCNA）蛋白的功能，通过赖氨酸甲基化。我们发现，SETD 8甲基化PCNA的赖氨酸248，无论是耗尽SETD 8或取代赖氨酸248不稳定的PCNA表达。机械上，赖氨酸甲基化显着增强PCNA和皮瓣核酸内切酶FEN 1之间的相互作用。PCNA甲基化的丧失延缓了冈崎片段的成熟，减慢了DNA复制，并诱导DNA损伤，表达甲基化失活的PCNA突变体的细胞更容易受到DNA损伤。癌细胞中甲基化PCNA表达增加，癌组织中SETD 8和PCNA的表达水平相关。总之，我们的研究结果揭示了非组蛋白赖氨酸甲基化的功能，并表明PCNA的异常赖氨酸甲基化可能在人类致癌中发挥作用。Cancer Res; 72（13）; 3217-27. (C)2012年AACR。
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. Cancer Res; 72(13); 3217-27. (C) 2012 AACR.