Mitotic-specific methylation of histone H4 Lys 20 follows increased PR-Set7 expression and its localization to mitotic chromosomes

Rice, Judd C.; Nishioka, Kusuki; Sarma, Kavitha; Steward, Ruth; Reinberg, Danny; Allis, C. David

doi:10.1101/gad.1014902

Cited by 228 publications

(232 citation statements)

References 30 publications

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“…The chromatin association of L3MBTL1 mirrors the progressive accumulation of H4K20me1 during the cell cycle The H4K20me1 modification is cell cycle regulated although the timing of its appearance and peak levels have varied among different cell types and experimental strategies (Fang et al, 2002;Rice et al, 2002;Pesavento et al, 2008). Therefore, we examined the levels of L3MBTL1 during distinct phases of the cell cycle, and using synchronized K562 cells, we found high levels of L3MBTL1 protein in G1/S and S phase cells, but barely detectable levels in G2/M cells (not shown).…”

Section: Recognition Of Histone Methyl Lysines By L3mbtl1mentioning

confidence: 99%

Histone H4 lysine 20 monomethylation promotes transcriptional repression by L3MBTL1

et al. 2008

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Lethal 3 malignant brain tumor 1 (L3MBTL1), a homolog of the Drosophila polycomb tumor suppressor l(3)mbt, contains three tandem MBT repeats (3xMBT) that are critical for transcriptional repression. We recently reported that the 3xMBT repeats interact with mono-and dimethylated lysines in the amino termini of histones H4 and H1b to promote methylation-dependent chromatin compaction. Using a series of histone peptides, we now show that the recognition of mono-and dimethylated lysines in histones H3, H4 and H1.4 (but not their trimethylated or unmodified counterparts) by 3xMBT occurs in the context of a basic environment, requiring a conserved aspartic acid (D355) in the second MBT repeat. Despite the broad range of in vitro binding, the chromatin association of L3MBTL1 mirrors the progressive accumulation of H4K20 monomethylation during the cell cycle. Furthermore, transcriptional repression by L3MBTL1 is enhanced by the H4K20 monomethyltransferase PR-SET7 (to which it binds) but not SUV420H1 (an H4K20 trimethylase) or G9a (an H3K9 dimethylase) and knockdown of PR-SET7 decreases H4K20me1 levels and the chromatin association of L3MBTL1. Our studies identify the importance of H4K20 monomethylation and of PR-SET7 for L3MBTL1 function.

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Section: Recognition Of Histone Methyl Lysines By L3mbtl1mentioning

confidence: 99%

Histone H4 lysine 20 monomethylation promotes transcriptional repression by L3MBTL1

et al. 2008

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“…Another scenario could be that the hMOFdepleted cells may have a defective S phase checkpoint, therefore leading to the observed G 2 /M accumulation. We can speculate that a hMOF-dependent reduction of H4K16 acetylation, a modification that reaches its highest levels during mid-S phase (Rice et al, 2002), could affect DNA replication, as during this phase a tight co-ordination between DNA replication and preservation of epigenetic integrity must be achieved (Groth et al, 2007). An alternative explanation would be that loss of hMOF could impair the cell's ability to repair DNA, thereby activating the G 2 /M checkpoint.…”

Section: Hmof In the Dna Damage Responsementioning

confidence: 99%

Males absent on the first (MOF): from flies to humans

2007

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Histone modifications such as acetylation, methylation and phosphorylation have been implicated in fundamental cellular processes such as epigenetic regulation of gene expression, organization of chromatin structure, chromosome segregation, DNA replication and DNA repair. Males absent on the first (MOF) is responsible for acetylating histone H4 at lysine 16 (H4K16) and is a key component of the MSL complex required for dosage compensation in Drosophila. The human ortholog of MOF (hMOF) has the same substrate specificity and recent purification of the human and Drosophila MOF complexes showed that these complexes were also highly conserved through evolution. Several studies have shown that loss of hMOF in mammalian cells leads to a number of different phenotypes; a G 2 /M cell cycle arrest, nuclear morphological defects, spontaneous chromosomal aberrations, reduced transcription of certain genes and an impaired DNA repair response upon ionizing irradiation. Moreover, hMOF is involved in ATM activation in response to DNA damage and acetylation of p53 by hMOF influences the cell's decision to undergo apoptosis instead of a cell cycle arrest. These data, highlighting hMOF as an important component of many cellular processes, as well as links between hMOF and cancer will be discussed.

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“…HeLa cells were synchronized at the G 1 /S border by a thymidine-mimosine double block (31). Cells were released from the block and collected every 2.5 h, and then flow cytometry was used to determine their phase in the cell cycle (supplemental Fig.…”

Section: Global Changes In H4k20 Methylation Occur During Cell Cyclementioning

confidence: 99%

“…Although the loss of PR-Set7 by RNAi eventually resulted in defective replication fork activity and delayed S phase progression, several cell cycles were required to achieve this phenotype (29,30). Furthermore, we previously demonstrated that expression of PR-Set7 was tightly cell cycleregulated where it was undetectable at G 1 /S, slowly increased during late S phase, and peaked during mitosis, concomitant with its catalytic activity (31). Based on these contradictory observations, it currently remains unclear how PR-Set7 and H4K20 methylation function in mammalian cell cycle progression.…”

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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

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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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Mitotic-specific methylation of histone H4 Lys 20 follows increased PR-Set7 expression and its localization to mitotic chromosomes

Cited by 228 publications

References 30 publications

Histone H4 lysine 20 monomethylation promotes transcriptional repression by L3MBTL1

Histone H4 lysine 20 monomethylation promotes transcriptional repression by L3MBTL1

Males absent on the first (MOF): from flies to humans

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

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