Histone Acetylation at the Replication Site

The re-establishment of the acetylation state of nucleosomes after DNA replication requires both deacetylation and acetylation of specific lysine residues on newly incorporated histones. Histone modifying enzymes interact with replication proteins such as the Origin Recognition Complex (ORC) that marks replication origins in eukaryotes and the Minichromosome Maintenance Complex (MCM), a multisubunit helicase composed of proteins MCM2-7 involved in DNA replication. In budding yeast, a histone acetyl-transferase called Sas2 (something about silencing 2) acetylates lysine 16 of histone H4 and is important to counteract gene silencing at the HMR locus and the rDNA but has opposite effects on silencing at the HML, and telomeric loci (Meijsing and Ehrenhofer-Murray 2001; Osada et al. 2001). Indeed, a mutation in histone H4 replacing K16 with R has a phenotype very similar to that of the sas2 deletion (Meijsing and Ehrenhofer-Murray 2001; Osada et al. 2001). This HAT interacts with the large subunit of CAF-1 (Cac1p) and ASF1 (Meijsing and Ehrenhofer-Murray 2001; Osada et al. 2001). These findings suggest that the role of Cac1p in epigenetic inheritance may be, at least in part, a result of its interaction with Sas2. In human cells, a highly related acetyltransferase named HBO1 (Histone acetyltransferase Bound to ORC 1) interacts with the DNA replication proteins ORC1 (Iizuka and Stillman 1999) and MCM2 (Burke et al. 2001). In Drosophila a protein called Chameau is the fly counterpart of HBO1 according to sequence analysis, and this putative his-tone acetyltransferase operates in epigenetic silencing mediated by pericen-tromeric heterochromatin and the Polycomb group transcriptional repressors (Grienenberger et al. 2002). The transcriptional co-activator p300 is yet another factor with histone acetyltransferase activity that interacts with a central component of the DNA replication and repair machinery, PCNA, and this interaction has been specifically linked to nucleotide excision repair-coupled DNA synthesis (Hasan et al. 2001). Together, these findings illustrate a close link between the replication machinery and histone acetyltransferases involved in gene regulation. Caveats to this interpretation may be that histone modifying enzymes may also modify other components of chromatin including the replication machinery itself, and that replication proteins such as the ORC complex may have functions outside of DNA replication (see, for example, Prasanth et al. 2002; Bailis and Forsburg 2003).

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