p53-Dependent Transcription and Tumor Suppression Are Not Affected in Set7/9-Deficient Mice

Lehnertz, Bernhard; Rogalski, Jason C.; Schulze, Felix; Lin, Yan; Lin, Shujun; Kast, Juergen; Rossi, Fábio

doi:10.1016/j.molcel.2011.08.006

Cited by 69 publications

(85 citation statements)

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“…64 The fact that the genetic abrogation of Set7/9 in non-transformed cells 7,8 does not affect their cell cycle or survival, makes Set7/9 a very attractive U2-OS cells with stable expression of shRNA against Set7/9 and p53 were obtained by lentiviral infection as described previously 16 (Lezina CDDs, 2013). U2-OS cells with inducible expression of shRNA against Set7/9 and the reference cell line were generated from the commercially available U2-OS Tet-On cells (Clontech/Takara Bio Company, Mountain View, CA, USA) stably transfected with pSuperior or pSuperior-shRNA-Set7/9, respectively.…”

Section: Discussionmentioning

confidence: 99%

“…Set7/9 was initially identified as a monomethylase of histone H3 lysine 4 (H3K4) in vitro. 4,5 However, we and others showed that the recombinant Set7/9 failed to target nucleosomes for methylation, [6][7][8] suggesting that Set7/9 functions as a factor-specific KMTase. There have been several non-histone proteins reported as the substrates for Set7/9, including TAF10 (TATA box binding protein (TBP)-associated factor, 30 kDa), 9 oestrogen receptor a (ERa), 10 RelA, 11 PCAF (P300/CBP-associated factor), 12 Stat3, 13 Yap, 14 and Suv39h1.…”

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confidence: 83%

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KMTase Set7/9 is a critical regulator of E2F1 activity upon genotoxic stress

et al. 2014

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During the recent years lysine methyltransferase Set7/9 ((Su(var)-3-9, Enhancer-of-Zeste, Trithorax) domain containing protein 7/9) has emerged as an important regulator of different transcription factors. In this study, we report a novel function for Set7/9 as a critical co-activator of E2 promoter-binding factor 1 (E2F1)-dependent transcription in response to DNA damage. By means of various biochemical, cell biology, and bioinformatics approaches, we uncovered that cell-cycle progression through the G1/S checkpoint of tumour cells upon DNA damage is defined by the threshold of expression of both E2F1 and Set7/9. The latter affects the activity of E2F1 by indirectly modulating histone modifications in the promoters of E2F1-dependent genes. Moreover, Set7/9 differentially affects E2F1 transcription targets: it promotes cell proliferation via expression of the CCNE1 gene and represses apoptosis by inhibiting the TP73 gene. Our biochemical screening of the panel of lung tumour cell lines suggests that these two factors are critically important for transcriptional upregulation of the CCNE1 gene product and hence successful progression through cell cycle. These findings identify Set7/9 as a potential biomarker in tumour cells with overexpressed E2F1 activity. Cell Death and Differentiation (2014) 21, 1889-1899; doi:10.1038/cdd.2014.108; published online 15 August 2014Lysine methylation of non-histone proteins has recently emerged as a novel regulatory mechanism to control protein functions. 1-4Set7/9 ((Su(var)-3-9, Enhancer-of-Zeste, Trithorax) domain containing protein 7/9) is a founding member of the family of non-chromatin lysine methyltransferases (KMTases). Set7/9 was initially identified as a monomethylase of histone H3 lysine 4 (H3K4) in vitro. 4,5However, we and others showed that the recombinant Set7/9 failed to target nucleosomes for methylation, [6][7][8] suggesting that Set7/9 functions as a factor-specific KMTase. There have been several non-histone proteins reported as the substrates for Set7/9, including TAF10 (TATA box binding protein (TBP)-associated factor, 30 kDa), 9 oestrogen receptor a (ERa), 10 RelA, 11 PCAF (P300/CBP-associated factor), 12 Stat3,13 Yap, 14 and Suv39h1. 15 However, in most cases the functional significance of this methylation is still not clear. The beststudied targets of Set7/9-mediated methylation are p53 16 and E2 promoter-binding factor 1 (E2F1), 17 transcription factors involved in regulation of DNA damage response (DDR).In response to genotoxic stress cancer cells undergo cell-cycle arrest either in G1/S or G2/M or in both checkpoints. The presence of intact p53 in cancer cells mediates transient G1/S checkpoint arrest, 18,19 which allows cells to repair the damaged DNA before replication or, if the amount of damage is insurmountable, drives cells into apoptosis. 20,21On the contrary, the activity of the E2F family transcription factors, especially E2F1, drives cells from the G1/S block to mitosis. 22,23 Transcriptional activity of E2F1, in turn, is repressed by the retin...

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Section: Discussionmentioning

confidence: 99%

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confidence: 83%

KMTase Set7/9 is a critical regulator of E2F1 activity upon genotoxic stress

et al. 2014

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“…SET7/9 also plays multiple roles in the DNA damage response by catalyzing the methylation of a series of nonhistone substrates such as p53, E2F transcription factor 1 (E2F1), and SIRT1 (22)(23)(24)(25)(26). Because SET7/9 and SUV39H1 exhibit similar properties in their responses to DNA damage, we were interested in investigating the possible coordination of these two histone methyltransferases in response to DNA damage.…”

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Methylation of SUV39H1 by SET7/9 results in heterochromatin relaxation and genome instability

Wang

Zhou

Liu

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

103

106

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Suppressor of variegation 3-9 homolog 1 (SUV39H1), a histone methyltransferase, catalyzes histone 3 lysine 9 trimethylation and is involved in heterochromatin organization and genome stability. However, the mechanism for regulation of the enzymatic activity of SUV39H1 in cancer cells is not yet well known. In this study, we identified SET domain-containing protein 7 (SET7/9), a protein methyltransferase, as a unique regulator of SUV39H1 activity. In response to treatment with adriamycin, a DNA damage inducer, SET7/9 interacted with SUV39H1 in vivo, and a GST pull-down assay confirmed that the chromodomain-containing region of SUV39H1 bound to SET7/9. Western blot using antibodies specific for antimethylated SUV39H1 and mass spectrometry demonstrated that SUV39H1 was specifically methylated at lysines 105 and 123 by SET7/9. Although the half-life and localization of methylated SUV39H1 were not noticeably changed, the methyltransferase activity of SUV39H1 was dramatically down-regulated when SUV39H1 was methylated by SET7/ 9. Consequently, H3K9 trimethylation in the heterochromatin decreased significantly, which, in turn, led to a significant increase in the expression of satellite 2 (Sat2) and α-satellite (α-Sat), indicators of heterochromatin relaxation. Furthermore, a micrococcal nuclease sensitivity assay and an immunofluorescence assay demonstrated that methylation of SUV39H1 facilitated genome instability and ultimately inhibited cell proliferation. Together, our data reveal a unique interplay between SET7/9 and SUV39H1-two histone methyltransferases-that results in heterochromatin relaxation and genome instability in response to DNA damage in cancer cells.histone methylation | nonhistone posttranslational modifications

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“…65 However, this observation is contradicted by an another study showing a lack of significance of SET7/9 methylation in p53 acetylation and transcriptional functions. 66 Dimethylation of K370 by a currently unidentified methylase is known to promote association of p53 to 53BP1 upon DNA damage. The demethylase LSD1 inhibits this association by removing methyl moieties from K370.…”

Section: Different Strokes For Different Folks: P53 Regulation Througmentioning

confidence: 99%

p53 regulation upon genotoxic stress: intricacies and complexities

Kumari

Kohli

Das

2014

Molecular & Cellular Oncology

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These authors contributed equally to this work.Keywords: cancer, genotoxic stress, miRNA, p53, post-translational modifications Abbreviations: miRNA, microRNA; ROS, reactive oxygen species; UTR, untranslated region p53, the revered savior of genomic integrity, receives signals from diverse stress sensors and strategizes to maintain cellular homeostasis. However, the predominance of p53 overshadows the fact that this herculean task is no one-man show; rather, there is a huge army of regulators that reign over p53 at various levels to avoid an unnecessary surge in its levels and sculpt it dynamically to favor one cellular outcome over another. This governance starts right at the time of p53 translation, which is gated by proteins that bind to p53 mRNA and keep a stringent check on p53 protein levels. The same effect is also achieved by ubiquitylases and deubiquitylases that fine-tune p53 turnover and miRNAs that modulate p53 levels, adding precision to this entire scheme. In addition, extensive covalent modifications and differential protein interactions allow p53 to trigger a tailor-made response for a given circumstance. To magnify the marvel, these various tiers of regulation operate simultaneously and in various combinations. In this review, we have tried to provide a glimpse into this bewildering labyrinth. We believe that further studies will result in a better understanding of p53 regulation and that new insights will help unravel many aspects of cancer biology.Regulation of any cellular pathway is essential to coordinate the heterogeneity and complexity of functions in multicellular organisms. Among the tumor suppressors, decoding the bewildering number of pathways that p53 is involved in has long been the holy grail of scientists. p53 is a master regulator that integrates signals from diverse nodes and thus it is of no surprise that it is the most commonly mutated gene in a huge array of cancers with varied origins. p53 has many weapons at its disposal to combat stress including cell cycle arrest, senescence, apoptosis, autophagy, and metabolic reprogramming. Paradoxically, some of the outcomes of p53 activation are disparate and contradictory, such as cell cycle arrest, which is prosurvival, versus apoptosis and senescence, which are directed toward eliminating irreversibly damaged cells. This indicates that p53 needs to be educated to sense the extent and type of damage and make an appropriate choice of the kind of response it is going to elicit. Extensive research on the regulation of p53 under diverse kinds of stresses including genotoxic stress, starvation, hypoxia, and oncogene activation clearly indicate that p53 protein is regulated at diverse levels, including synthesis, degradation, covalent modifications, subcellular localization, and differential interaction with other proteins. Moreover, all possible permutations and combinations of these are employed to modulate p53 specificity, tissue heterogeneity, and diversity of function. In light of this, we restrict this review to exclusively dis...

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p53-Dependent Transcription and Tumor Suppression Are Not Affected in Set7/9-Deficient Mice

Cited by 69 publications

References 32 publications

KMTase Set7/9 is a critical regulator of E2F1 activity upon genotoxic stress

KMTase Set7/9 is a critical regulator of E2F1 activity upon genotoxic stress

Methylation of SUV39H1 by SET7/9 results in heterochromatin relaxation and genome instability

p53 regulation upon genotoxic stress: intricacies and complexities

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