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Association with the origin recognition complex suggests a novel role for histone acetyltransferase Hat1p/Hat2p.

Suter B, Pogoutse O, Guo X, Krogan N, Lewis P, Greenblatt JF, Rine J, Emili A - BMC Biol. (2007)

Bottom Line: While mutational inactivation of the histone acetyltransferase (HAT) gene HAT1 alone does not compromise origin firing or initiation of DNA replication, a deletion in HAT1 (or HAT2) exacerbates the growth defects of conditional orc-ts mutants.Thus, the ORC-associated Hat1p-dependent histone acetyltransferase activity suggests a novel linkage between histone modification and DNA replication.We have found an intriguing new association of the Hat1p-dependent histone acetyltransferase in addition to its previously known role in nuclear chromatin assembly (Hat1p/Hat2p-Hif1p).

View Article: PubMed Central - HTML - PubMed

Affiliation: Program in Proteomics and Bioinformatics, Banting and Best Department of Medical Genetics, University of Toronto, Toronto, Ontario, Canada. bernhard.suter@utoronto.ca

ABSTRACT

Background: Histone modifications have been implicated in the regulation of transcription and, more recently, in DNA replication and repair. In yeast, a major conserved histone acetyltransferase, Hat1p, preferentially acetylates lysine residues 5 and 12 on histone H4.

Results: Here, we report that a nuclear sub-complex consisting of Hat1p and its partner Hat2p interacts physically and functionally with the origin recognition complex (ORC). While mutational inactivation of the histone acetyltransferase (HAT) gene HAT1 alone does not compromise origin firing or initiation of DNA replication, a deletion in HAT1 (or HAT2) exacerbates the growth defects of conditional orc-ts mutants. Thus, the ORC-associated Hat1p-dependent histone acetyltransferase activity suggests a novel linkage between histone modification and DNA replication. Additional genetic and biochemical evidence points to the existence of partly overlapping histone H3 acetyltransferase activities in addition to Hat1p/Hat2p for proper DNA replication efficiency. Furthermore, we demonstrated a dynamic association of Hat1p with chromatin during S-phase that suggests a role of this enzyme at the replication fork.

Conclusion: We have found an intriguing new association of the Hat1p-dependent histone acetyltransferase in addition to its previously known role in nuclear chromatin assembly (Hat1p/Hat2p-Hif1p). The participation of a distinct Hat1p/Hat2p sub-complex suggests a linkage of histone H4 modification with ORC-dependent DNA replication.

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Related in: MedlinePlus

The current view on the different associations of Hat1p within the cell. In addition to the cytoplasmic Hat1p/Hat2p complex, the Hat1p/Hat2p-Hif1p chromatin assembly complex is recruited to chromatin during S-phase. A minor fraction of Hat1p/Hat2p is constitutively associated with ORC and presumably chromatin-bound. Additional H3-specific acetylation and additional substrates for Hat1p are possible.
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Figure 9: The current view on the different associations of Hat1p within the cell. In addition to the cytoplasmic Hat1p/Hat2p complex, the Hat1p/Hat2p-Hif1p chromatin assembly complex is recruited to chromatin during S-phase. A minor fraction of Hat1p/Hat2p is constitutively associated with ORC and presumably chromatin-bound. Additional H3-specific acetylation and additional substrates for Hat1p are possible.

Mentions: In addition to histone maturation in the cytoplasm and nucleosome assembly in the nucleus, our data now suggests an additional role for Hat1p through a direct interaction with ORC (Figure 9) that is distinct from its role as a subunit in the Hif1p-dependent chromatin assembly complex. The previously described roles of Hat1p and Hat2p in telomeric gene silencing and double-strand break-repair involved also the Hif1p chromatin assembly factor [28]. Like the association of ORC subunits with chromatin, the interaction of ORC with Hat1p is constitutive during the cell cycle. Based on the cumulative evidence gathered so far, we presume that Hat1p and Hat2p may enhance ORC function by contributing either to the overall efficiency of origin usage or through alteration of the chromatin structure of a specific subset of origins, most likely through acetylation of lysine residues 5 and 12 on histone H4. Although we have not identified the exact mechanism involved, the description of a Hat1p/Hat2p-ORC complex is consistent with an emerging expansive view of histone modifications as critical determinants of DNA metabolism [15,23,24].


Association with the origin recognition complex suggests a novel role for histone acetyltransferase Hat1p/Hat2p.

Suter B, Pogoutse O, Guo X, Krogan N, Lewis P, Greenblatt JF, Rine J, Emili A - BMC Biol. (2007)

The current view on the different associations of Hat1p within the cell. In addition to the cytoplasmic Hat1p/Hat2p complex, the Hat1p/Hat2p-Hif1p chromatin assembly complex is recruited to chromatin during S-phase. A minor fraction of Hat1p/Hat2p is constitutively associated with ORC and presumably chromatin-bound. Additional H3-specific acetylation and additional substrates for Hat1p are possible.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2140264&req=5

Figure 9: The current view on the different associations of Hat1p within the cell. In addition to the cytoplasmic Hat1p/Hat2p complex, the Hat1p/Hat2p-Hif1p chromatin assembly complex is recruited to chromatin during S-phase. A minor fraction of Hat1p/Hat2p is constitutively associated with ORC and presumably chromatin-bound. Additional H3-specific acetylation and additional substrates for Hat1p are possible.
Mentions: In addition to histone maturation in the cytoplasm and nucleosome assembly in the nucleus, our data now suggests an additional role for Hat1p through a direct interaction with ORC (Figure 9) that is distinct from its role as a subunit in the Hif1p-dependent chromatin assembly complex. The previously described roles of Hat1p and Hat2p in telomeric gene silencing and double-strand break-repair involved also the Hif1p chromatin assembly factor [28]. Like the association of ORC subunits with chromatin, the interaction of ORC with Hat1p is constitutive during the cell cycle. Based on the cumulative evidence gathered so far, we presume that Hat1p and Hat2p may enhance ORC function by contributing either to the overall efficiency of origin usage or through alteration of the chromatin structure of a specific subset of origins, most likely through acetylation of lysine residues 5 and 12 on histone H4. Although we have not identified the exact mechanism involved, the description of a Hat1p/Hat2p-ORC complex is consistent with an emerging expansive view of histone modifications as critical determinants of DNA metabolism [15,23,24].

Bottom Line: While mutational inactivation of the histone acetyltransferase (HAT) gene HAT1 alone does not compromise origin firing or initiation of DNA replication, a deletion in HAT1 (or HAT2) exacerbates the growth defects of conditional orc-ts mutants.Thus, the ORC-associated Hat1p-dependent histone acetyltransferase activity suggests a novel linkage between histone modification and DNA replication.We have found an intriguing new association of the Hat1p-dependent histone acetyltransferase in addition to its previously known role in nuclear chromatin assembly (Hat1p/Hat2p-Hif1p).

View Article: PubMed Central - HTML - PubMed

Affiliation: Program in Proteomics and Bioinformatics, Banting and Best Department of Medical Genetics, University of Toronto, Toronto, Ontario, Canada. bernhard.suter@utoronto.ca

ABSTRACT

Background: Histone modifications have been implicated in the regulation of transcription and, more recently, in DNA replication and repair. In yeast, a major conserved histone acetyltransferase, Hat1p, preferentially acetylates lysine residues 5 and 12 on histone H4.

Results: Here, we report that a nuclear sub-complex consisting of Hat1p and its partner Hat2p interacts physically and functionally with the origin recognition complex (ORC). While mutational inactivation of the histone acetyltransferase (HAT) gene HAT1 alone does not compromise origin firing or initiation of DNA replication, a deletion in HAT1 (or HAT2) exacerbates the growth defects of conditional orc-ts mutants. Thus, the ORC-associated Hat1p-dependent histone acetyltransferase activity suggests a novel linkage between histone modification and DNA replication. Additional genetic and biochemical evidence points to the existence of partly overlapping histone H3 acetyltransferase activities in addition to Hat1p/Hat2p for proper DNA replication efficiency. Furthermore, we demonstrated a dynamic association of Hat1p with chromatin during S-phase that suggests a role of this enzyme at the replication fork.

Conclusion: We have found an intriguing new association of the Hat1p-dependent histone acetyltransferase in addition to its previously known role in nuclear chromatin assembly (Hat1p/Hat2p-Hif1p). The participation of a distinct Hat1p/Hat2p sub-complex suggests a linkage of histone H4 modification with ORC-dependent DNA replication.

Show MeSH
Related in: MedlinePlus