Modulation of p53 Function by SET8-Mediated Methylation at Lysine 382

Shi, Xiaobing; Kachirskaia, Ioulia; Yamaguchi, Hiroshi; West, Lisandra; Wen, Hong; Wang, Evelyn W.; Dutta, Sucharita; Appella, Ettore; Gozani, Or

doi:10.1016/j.molcel.2007.07.012

Cited by 395 publications

(446 citation statements)

References 39 publications

(55 reference statements)

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“…In contrast, we demonstrated that the absence of PR-Set7 and its enzymatic function in human cells results in the activation of ATM and an associated significant increase in damaged DNA. Because PR-Set7 was recently shown to also methylate p53 and regulate its function (47), it was highly likely that the observed cell cycle arrest and activation of DNA damage pathways in the absence of PR-Set7 was due to altered p53 function. However, in the paired wild type and p53 Ϫ/Ϫ HCT116 cells lacking PR-Set7 enzymatic function, we observed the identical cell cycle defects and DNA damage regardless of p53 status, indicating that p53 methylation by PR-Set7 is not responsible for these phenotypes.…”

Section: Discussionmentioning

confidence: 99%

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Catalytic Function of the PR-Set7 Histone H4 Lysine 20 Monomethyltransferase Is Essential for Mitotic Entry and Genomic Stability

Houston

McManus

Adams

et al. 2008

Journal of Biological Chemistry

142

169

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Histone-modifying enzymes play a critical role in modulating chromatin dynamics. In this report we demonstrate that one of these enzymes, PR-Set7, and its corresponding histone modification, the monomethylation of histone H4 lysine 20 (H4K20), display a distinct cell cycle profile in mammalian cells: low at G 1 , increased during late S phase and G 2 , and maximal from prometaphase to anaphase. The lack of PR-Set7 and monomethylated H4K20 resulted in a number of aberrant phenotypes in several different mammalian cell types. These include the inability of cells to progress past G 2 , global chromosome condensation failure, aberrant centrosome amplification, and substantial DNA damage. By employing a catalytically dead dominant negative PR-Set7 mutant, we discovered that its mono-methyltransferase activity was required to prevent these phenotypes. Importantly, we demonstrate that all of the aberrant phenotypes associated with the loss of PR-Set7 enzymatic function occur independently of p53. Collectively, our findings demonstrate that PR-Set7 enzymatic activity is essential for mammalian cell cycle progression and for the maintenance of genomic stability, most likely by monomethylating histone H4K20. Our results predict that alterations of this pathway could result in gross chromosomal aberrations and aneuploidy.Dynamic alterations in chromatin structure are modulated, in part, by the post-translational modifications of the DNAassociated histone proteins. Specialized chromatin-modifying enzymes can phosphorylate, acetylate, ubiquitylate, or methylate specific amino acids within certain histones, and each of these modifications are associated with distinct biological events (1). One of the first histone modifications to be identified nearly forty-five years ago was the methylation of histone H4 lysine 20 (H4K20) 4 (2). Earlier biochemical studies linked H4K20 methylation to diverse biological events including transcriptional regulation, chromatin compaction, cell division, and the formation of heterochromatin (3-9). Importantly, it was also found that H4K20 is differentially methylated in vivo and therefore can be either mono-, di-, or trimethylated (10). Together, these findings strongly suggest that different methylated states of H4K20 may be involved in distinct biological processes, similar to what is observed for the various methylated states of histone H3 lysine 4 and 9 methylation (11, 12).Increasing evidence indicates that certain enzymes are responsible for the specific degree of histone lysine methylation (13). For example, the mono-and dimethylation of histone H3 lysine 9 in humans is mediated by the G9a enzyme, whereas trimethylation is mediated by the SUV39H1 enzyme (14,15). Similarly, the Suv4 -20 enzymes are responsible for di-and trimethylation in mammals (16,17). Trimethylated H4K20 is associated with repressed chromatin because it is targeted to constitutive heterochromatin, various repetitive elements, and imprinting control regions (16,18,19). Dimethylated H4K40 is more widely distributed within...

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Section: Discussionmentioning

confidence: 99%

“…Occur Independently of p53-It was recently reported that PRSet7 can monomethylate p53 in vivo and negatively regulate its function (47). The report showed that the lack of PR-Set7 enhanced the proapoptotic and cell cycle checkpoint functions of p53.…”

Section: Aberrant Phenotypes Associated With the Absence Of Pr-set7mentioning

confidence: 98%

Catalytic Function of the PR-Set7 Histone H4 Lysine 20 Monomethyltransferase Is Essential for Mitotic Entry and Genomic Stability

Houston

McManus

Adams

et al. 2008

Journal of Biological Chemistry

142

169

View full text Add to dashboard Cite

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“…The siRNA sequences used were: TP53 (5 0 -GAAAUUUGCGUGUGGAGUAUU-3 0 ; ref. 21), CDKN1A (5 0 -CAGGCGGUUAUGAAAUUCA-3 0 ), and Luciferase (GL2; 5 0 -CGUACGCGGAAUACUUCGA-3 0 ). Reagents were purchased from the following suppliers: camptothecin, nocodazole, and MG132 were from Sigma, and FdUrd, FTD, and oxaliplatin were from Tokyo Chemical Industry.…”

Section: Cell Culture and Reagentsmentioning

confidence: 99%

Trifluridine Induces p53-Dependent Sustained G2 Phase Arrest with Its Massive Misincorporation into DNA and Few DNA Strand Breaks

Matsuoka

Iimori

Niimi

et al. 2015

Molecular Cancer Therapeutics

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Trifluridine (FTD) is a key component of the novel oral antitumor drug TAS-102, which consists of FTD and a thymidine phosphorylase inhibitor. Like 5-fluoro-2 0 -deoxyuridine (FdUrd), a deoxynucleoside form of 5-fluorouracil metabolite, FTD is sequentially phosphorylated and not only inhibits thymidylate synthase activity, but is also incorporated into DNA. Although TAS-102 was effective for the treatment of refractory metastatic colorectal cancer in clinical trials, the mechanism of FTDinduced cytotoxicity is not completely understood. Here, we show that FTD as well as FdUrd induce transient phosphorylation of Chk1 at Ser345, and that this is followed by accumulation of p53 and p21 proteins in p53-proficient human cancer cell lines. In particular, FTD induced p53-dependent sustained arrest at G 2 phase, which was associated with a proteasome-dependent decrease in the Cyclin B1 protein level and the suppression of CCNB1 and CDK1 gene expression. In addition, a p53-dependent increase in p21 protein was associated with an FTD-induced decrease in Cyclin B1 protein. Although numerous ssDNA and dsDNA breaks were induced by FdUrd, few DNA strand breaks were detected in FTD-treated HCT-116 cells despite massive FTD misincorporation into genomic DNA, suggesting that the antiproliferative effect of FTD is not due to the induction of DNA strand breaks. These distinctive effects of FTD provide insights into the cellular mechanism underlying its antitumor effect and may explain the clinical efficacy of TAS-102.

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“…Although histones are major substrates for histonemodifying enzymes such as HATs and HMTs, it is widely known that histone-modifying enzymes have nonhistone substrates, such as p53 (Shi et al 2007). In contrast, ATPdependent chromatin remodeling complexes have only been shown to remodel nucleosomes through their ability to disrupt DNA-histone interactions.…”

Section: Nonchromatin Substrates For Atp-dependent Chromatin Remodelimentioning

confidence: 99%

Regulation of Mec1 kinase activity by the SWI/SNF chromatin remodeling complex

et al. 2015

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ATP-dependent chromatin remodeling complexes alter chromatin structure through interactions with chromatin substrates such as DNA, histones, and nucleosomes. However, whether chromatin remodeling complexes have the ability to regulate nonchromatin substrates remains unclear. Saccharomyces cerevisiae checkpoint kinase Mec1 (ATR in mammals) is an essential master regulator of genomic integrity. Here we found that the SWI/SNF chromatin remodeling complex is capable of regulating Mec1 kinase activity. In vivo, Mec1 activity is reduced by the deletion of Snf2, the core ATPase subunit of the SWI/SNF complex. SWI/SNF interacts with Mec1, and cross-linking studies revealed that the Snf2 ATPase is the main interaction partner for Mec1. In vitro, SWI/SNF can activate Mec1 kinase activity in the absence of chromatin or known activators such as Dpb11. The subunit requirement of SWI/SNFmediated Mec1 regulation differs from that of SWI/SNF-mediated chromatin remodeling. Functionally, SWI/SNFmediated Mec1 regulation specifically occurs in S phase of the cell cycle. Together, these findings identify a novel regulator of Mec1 kinase activity and suggest that ATP-dependent chromatin remodeling complexes can regulate nonchromatin substrates such as a checkpoint kinase.

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Modulation of p53 Function by SET8-Mediated Methylation at Lysine 382

Cited by 395 publications

References 39 publications

Catalytic Function of the PR-Set7 Histone H4 Lysine 20 Monomethyltransferase Is Essential for Mitotic Entry and Genomic Stability

Catalytic Function of the PR-Set7 Histone H4 Lysine 20 Monomethyltransferase Is Essential for Mitotic Entry and Genomic Stability

Trifluridine Induces p53-Dependent Sustained G2 Phase Arrest with Its Massive Misincorporation into DNA and Few DNA Strand Breaks

Regulation of Mec1 kinase activity by the SWI/SNF chromatin remodeling complex

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