Regulation of heterochromatic DNA replication by histone H3 lysine 27 methyltransferases. Nature

Department of Biology, Indiana University, 915 East Third Street, Bloomington, Indiana 47405, USA.
Nature (Impact Factor: 41.46). 08/2010; 466(7309):987-91. DOI: 10.1038/nature09290
Source: PubMed


Multiple pathways prevent DNA replication from occurring more than once per cell cycle. These pathways block re-replication by strictly controlling the activity of pre-replication complexes, which assemble at specific sites in the genome called origins. Here we show that mutations in the homologous histone 3 lysine 27 (H3K27) monomethyltransferases, ARABIDOPSIS TRITHORAX-RELATED PROTEIN5 (ATXR5) and ATXR6, lead to re-replication of specific genomic locations. Most of these locations correspond to transposons and other repetitive and silent elements of the Arabidopsis genome. These sites also correspond to high levels of H3K27 monomethylation, and mutation of the catalytic SET domain is sufficient to cause the re-replication defect. Mutation of ATXR5 and ATXR6 also causes upregulation of transposon expression and has pleiotropic effects on plant development. These results uncover a novel pathway that prevents over-replication of heterochromatin in Arabidopsis.

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Available from: Yannick Jacob, Apr 22, 2014
    • "H3K27me1, a typical mark of heterochromatin , is deposited by the methyltransferases ATXR5 and ATXR6 (ARABIDOPSIS TRITHORAX RELATED PROTEIN 5 and 6), which are transcriptional E2F targets and interactors of PCNA (Raynaud et al., 2006; Jacob et al., 2009). Leaf cells of the atxr5 atxr6 double mutant show a significant increase in the content of pericentromeric sequences, as revealed by deep sequencing of genomic DNA extracted from nuclei of various ploidy levels (Jacob et al., 2010). As a large fraction of extra DNA is located at specific loci within heterochromatic regions it seems that a certain level of H3K27me1 is needed to prevent heterochromatin re-replication. "

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    • "There is close coordination between DNA methylation, chromatin structure, DNA synthesis and replication timing. DNA replication origins fire first from euchromatin, and heterochromatin protects against re-firing (Dorn and Cook, 2011), as shown in Arabidopsis thaliana, where the maintenance of heterochromatin protects against re-replication (Jacob et al., 2010; Stroud et al., 2012) and possibly even endoreplication (Jegu et al., 2013). Thus, loss of Uhrf1 may alleviate a block to DNA re-replication, causing uncoordinated replication. "

    Full-text · Article · Jan 2015 · Development
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    • "Less speculative is the role of H3K27me1 in controlling re-replication in Arabidopsis heterochromatin. This has been demonstrated using mutant plants lacking the ATXR5 and ATXR6 genes encoding the Trithorax-related H3K27 monomethyltransferases that exhibit abnormal re-replication control of the heterochromatin domains (Jacob et al., 2009, 2010). Furthermore, decreased methylation of cytosines suppresses the phenotype of the double atxr5, atxr6 mutant (Stroud et al., 2012a). "
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    ABSTRACT: The cell cycle is defined by a series of complex events, finely coordinated through hormonal, developmental and environmental signals, which occur in a unidirectional manner and end up in producing two daughter cells. Accumulating evidence reveals that chromatin is not a static entity throughout the cell cycle. In fact, there are many changes that include nucleosome remodeling, histone modifications, deposition and exchange, among others. Interestingly, it is possible to correlate the occurrence of several of these chromatin-related events with specific processes necessary for cell cycle progression, e.g., licensing of DNA replication origins, the E2F-dependent transcriptional wave in G1, the activation of replication origins in S-phase, the G2-specific transcription of genes required for mitosis or the chromatin packaging occurring in mitosis. Therefore, an emerging view is that chromatin dynamics must be considered as an intrinsic part of cell cycle regulation. In this article, we review the main features of several key chromatin events that occur at defined times throughout the cell cycle and discuss whether they are actually controlling the transit through specific cell cycle stages.
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