Article

HBO1 links p53-dependent stress signaling to DNA replication licensing

Department of Microbiology, University of Virginia Health System, P.O. Box 800734, Charlottesville, VA 22908-0734, USA.
Molecular and Cellular Biology (Impact Factor: 5.04). 02/2008; 28(1):140-53. DOI: 10.1128/MCB.00662-07
Source: PubMed

ABSTRACT Hbo1 is a histone acetyltransferase (HAT) that is required for global histone H4 acetylation, steroid-dependent transcription, and chromatin loading of MCM2-7 during DNA replication licensing. It is the catalytic subunit of protein complexes that include ING and JADE proteins, growth regulatory factors and candidate tumor suppressors. These complexes are thought to act via tumor suppressor p53, but the molecular mechanisms and links between stress signaling and chromatin, are currently unknown. Here, we show that p53 physically interacts with Hbo1 and negatively regulates its HAT activity in vitro and in cells. Two physiological stresses that stabilize p53, hyperosmotic shock and DNA replication fork arrest, also inhibit Hbo1 HAT activity in a p53-dependent manner. Hyperosmotic stress during G(1) phase specifically inhibits the loading of the MCM2-7 complex, providing an example of the chromatin output of this pathway. These results reveal a direct regulatory connection between p53-responsive stress signaling and Hbo1-dependent chromatin pathways.

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    • "Several observations suggest the importance of H4 acetylation for licensing. First, HBO1 is the predominant H4 acetylase in human cells (Figure 2A (Iizuka et al., 2008), and it is recruited to origins at the time of licensing, where it is important for loading the MCM complex (Miotto and Struhl, 2008). Second, treatments of cells that either increase (overexpression of HBO1 and Jade-1) or decrease (Set8-HBD overexpression) H4 acetylation reveal a correlation between levels of bulk H4 acetylation and MCM complex loading (Figures 4, 5). "
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    ABSTRACT: HBO1, an H4-specific histone acetylase, is a coactivator of the DNA replication licensing factor Cdt1. HBO1 acetylase activity is required for licensing, because a histone acetylase (HAT)-defective mutant of HBO1 bound at origins is unable to load the MCM complex. H4 acetylation at origins is cell-cycle regulated, with maximal activity at the G1/S transition, and coexpression of HBO1 and Jade-1 increases histone acetylation and MCM complex loading. Overexpression of the Set8 histone H4 tail-binding domain specifically inhibits MCM loading, suggesting that histones are a physiologically relevant target for licensing. Lastly, Geminin inhibits HBO1 acetylase activity in the context of a Cdt1-HBO1 complex, and it associates with origins and inhibits H4 acetylation and licensing in vivo. Thus, H4 acetylation at origins by HBO1 is critical for replication licensing by Cdt1, and negative regulation of licensing by Geminin is likely to involve inhibition of HBO1 histone acetylase activity.
    Molecular cell 01/2010; 37(1):57-66. DOI:10.1016/j.molcel.2009.12.012 · 14.46 Impact Factor
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    • "In addition to myriad p53-binding proteins, several new proteins have been identified that can also bind and regulate p53 but have yet to be shown to impart any selectivity to p53 target gene activation. Among these proteins are Sug1, a component of the 19S proteasome (Zhu et al., 2007), heterogeneous ribonucleoprotein particle K (hnRNPK), which possibly acts through Mdm2 (Moumen et al., 2005), Hbo1 (Iizuka et al., 2008), KLF5 (Zhu et al., 2006), NF-Y (Imbriano et al., 2005), clathrin heavy chain (Enari et al., 2006), and the orphan receptor TR3 (Zhao et al., 2006). We will be very curious to learn whether any of these proteins exert promoter-selective effects on p53's transactivation capabilities. "
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    ABSTRACT: While the tumor suppressor functions of p53 have long been recognized, the contribution of p53 to numerous other aspects of disease and normal life is only now being appreciated. This burgeoning range of responses to p53 is reflected by an increasing variety of mechanisms through which p53 can function, although the ability to activate transcription remains key to p53's modus operandi. Control of p53's transcriptional activity is crucial for determining which p53 response is activated, a decision we must understand if we are to exploit efficiently the next generation of drugs that selectively activate or inhibit p53.
    Cell 06/2009; 137(3):413-31. DOI:10.1016/j.cell.2009.04.037 · 33.12 Impact Factor
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    • "His-tagged Hbol (Iizuka et al., 2008) was expressed in bacteria BL21(DE3)-RIL (Strata-gene) and purified on heparin sepharose (Amersham Pharmacia) and Ni-NTA-agarose (Qiagen). HAT assays were performed as reported previously (Iizuka and Stillman, 1999), except for the use of chicken core histones in this study. "
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    ABSTRACT: In addition to the well-characterized proteins that comprise the pre-replicative complex, recent studies suggest that chromatin structure plays an important role in DNA replication initiation. One of these chromatin factors is the histone acetyltransferase (HAT) Hbo1 which is unique among HAT enzymes in that it serves as a positive regulator of DNA replication. However, several of the basic properties of Hbo1 have not been previously examined, including its intrinsic catalytic activity, its molecular abundance in cells, and its pattern of expression in primary cancer cells. Here we show that recombinant Hbo1 can acetylate nucleosomal histone H4 in vitro, with a preference for lysines 5 and 12. Using semi-quantitative western blot analysis, we find that Hbo1 is approximately equimolar with the number of active replication origins in normal human fibroblasts but is an order of magnitude more abundant in both MCF7 and Saos-2 established cancer cell lines. Immunohistochemistry for Hbo1 in 11 primary human tumor types revealed strong Hbo1 protein expression in carcinomas of the testis, ovary, breast, stomach/esophagus, and bladder.
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