Direct interaction between SET8 and PCNA couples H4-K20 methylation with DNA replication

Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 05/2008; 283(17):11073-7. DOI: 10.1074/jbc.C700242200
Source: PubMed


Chromatin endowed by histone modifications governs chromatin structure, which in turn represents a means to regulate cellular
processes, including transcription and heterochromatin formation. Recent evidence revealed a plethora of enzymes that catalyze
specific histone modifications for epigenetic maintenance, and dysregulation of which contributes to tumorigenesis and developmental
defects. The histone methyltransferase SET8 (also known as Pr-Set7) was previously reported to monomethylate Lys20 of histone H4. However, the temporal and spatial control of SET8 activity remains elusive. Here, we provide evidence to support
that SET8 monomethylates Lys20 of histone H4 during S phase by tethering to proliferating cell nuclear antigen via a putative proliferating cell nuclear
antigen-interacting protein box. In addition, we show that SET8 function is required for S phase progression. Finally, deletion
of SET8 in mice causes embryonic lethality, suggesting that SET8 plays an important role in mammalian embryogenesis.

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    • "The link between histone H4 HMTs and genomic maintenance became evident when these enzymes were depleted by siRNA in human cell lines and removed genetically in experimental animal models. Genetic ablation of SET8 results in lethality in both fly (22) and mouse (11,23). RNA interference of SET8 also has severe consequences for the cells resulting in DNA double-strand breaks (DSBs), activation of DNA damage checkpoints, defective cell cycle progression and reduced cell proliferation (11,14,15,22,24). "
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    ABSTRACT: Maintenance of genomic integrity is essential to ensure normal organismal development and to prevent diseases such as cancer. Nuclear DNA is packaged into chromatin, and thus genome maintenance can be influenced by distinct chromatin environments. In particular, post-translational modifications of histones have emerged as key regulators of genomic integrity. Intense research during the past few years has revealed histone H4 lysine 20 methylation (H4K20me) as critically important for the biological processes that ensure genome integrity, such as DNA damage repair, DNA replication and chromatin compaction. The distinct H4K20 methylation states are mediated by SET8/PR-Set7 that catalyses monomethylation of H4K20, whereas SUV4-20H1 and SUV4-20H2 enzymes mediate further H4K20 methylation to H4K20me2 and H4K20me3. Disruption of these H4K20-specific histone methyltransferases leads to genomic instability, demonstrating the important functions of H4K20 methylation in genome maintenance. In this review, we explain molecular mechanisms underlying these defects and discuss novel ideas for furthering our understanding of genome maintenance in higher eukaryotes.
    Full-text · Article · Jan 2013 · Nucleic Acids Research
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    • "If the HMTs E(z) and Trx were stable to passage of the RF and DNA polymerase, they could methylate newly synthesized histones to re-establish the parental pattern of histone modifications on nascent DNA. Consistent with this model, Set8, an H4K20 monomethylase, is targeted to RFs through a direct interaction with PCNA (Huen et al., 2008), and a complex containing SetDB1-MBD1-CAF-1 that trimethylates H3K9 is recruited by hemimethylated DNA (Sarraf and Stancheva, 2004). An attractive alternative model is based on observations that parental histones are transferred randomly to nascent DNA (Jackson and Chalkley, 1985). "
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    ABSTRACT: Propagation of gene-expression patterns through the cell cycle requires the existence of an epigenetic mark that re-establishes the chromatin architecture of the parental cell in the daughter cells. We devised assays to determine which potential epigenetic marks associate with epigenetic maintenance elements during DNA replication in Drosophila embryos. Histone H3 trimethylated at lysines 4 or 27 is present during transcription but, surprisingly, is replaced by nonmethylated H3 following DNA replication. Methylated H3 is detected on DNA only in nuclei not in S phase. In contrast, the TrxG and PcG proteins Trithorax and Enhancer-of-Zeste, which are H3K4 and H3K27 methylases, and Polycomb continuously associate with their response elements on the newly replicated DNA. We suggest that histone modification enzymes may re-establish the histone code on newly assembled unmethylated histones and thus may act as epigenetic marks.
    Full-text · Article · Aug 2012 · Cell
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    • "Of note, after inhibition of proteasome-mediated degradation, PR-Set7 localizes to sites of active DNA replication (Tardat et al. 2007). Further insights into PR-Set7 function during DNA replication emerged through the study of its individual domains, specifically its PIP domain (Jorgensen et al. 2007; Huen et al. 2008). Stabilization of PR-Set7 during S phase by mutation of its PIP domain causes a cell cycle arrest in the G2 phase, with a concomitant decrease in the S-phase population (Abbas et al. 2010; Centore et al. 2010). "
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    ABSTRACT: Histone post-translational modifications impact many aspects of chromatin and nuclear function. Histone H4 Lys 20 methylation (H4K20me) has been implicated in regulating diverse processes ranging from the DNA damage response, mitotic condensation, and DNA replication to gene regulation. PR-Set7/Set8/KMT5a is the sole enzyme that catalyzes monomethylation of H4K20 (H4K20me1). It is required for maintenance of all levels of H4K20me, and, importantly, loss of PR-Set7 is catastrophic for the earliest stages of mouse embryonic development. These findings have placed PR-Set7, H4K20me, and proteins that recognize this modification as central nodes of many important pathways. In this review, we discuss the mechanisms required for regulation of PR-Set7 and H4K20me1 levels and attempt to unravel the many functions attributed to these proteins.
    Full-text · Article · Feb 2012 · Genes & development
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