The BAH domain of ORC1 links H4K20me2 to DNA replication licensing and Meier–Gorlin syndrome
The ORC1 BAH domain is shown to be a module that recognizes a histone modification associated with replication origins, providing insight into the aetiology of Meier–Gorlin syndrome. Histone methylation linked to DNA replication ORC1 is a subunit of the replication-licensing machinery that associate...
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Veröffentlicht in: | Nature 2012-04, Vol.484 (7392), p.115-119 |
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Sprache: | eng |
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Zusammenfassung: | The ORC1 BAH domain is shown to be a module that recognizes a histone modification associated with replication origins, providing insight into the aetiology of Meier–Gorlin syndrome.
Histone methylation linked to DNA replication
ORC1 is a subunit of the replication-licensing machinery that associates with replication origins, and mutations in the ORC1 BAH domain have been associated with a dwarfism syndrome. Here, the ORC1 BAH domain is shown to comprise a module that recognizes a histone modification associated with replication origins. Insight into the molecular basis of the interaction is provided by a crystal structure. The interaction between ORC1 BAH domain and the histone modification is required for loading of ORC onto chromatin, and is also required to prevent dwarfism in a zebrafish model of the disease.
The recognition of distinctly modified histones by specialized ‘effector’ proteins constitutes a key mechanism for transducing molecular events at chromatin to biological outcomes
1
. Effector proteins influence DNA-templated processes, including transcription, DNA recombination and DNA repair; however, no effector functions have yet been identified within the mammalian machinery that regulate DNA replication. Here we show that ORC1—a component of ORC (origin of replication complex), which mediates pre-DNA replication licensing
2
—contains a bromo adjacent homology (BAH) domain that specifically recognizes histone H4 dimethylated at lysine 20 (H4K20me2). Recognition of H4K20me2 is a property common to BAH domains present within diverse metazoan ORC1 proteins. Structural studies reveal that the specificity of the BAH domain for H4K20me2 is mediated by a dynamic aromatic dimethyl-lysine-binding cage and multiple intermolecular contacts involving the bound peptide. H4K20me2 is enriched at replication origins, and abrogating ORC1 recognition of H4K20me2 in cells impairs ORC1 occupancy at replication origins, ORC chromatin loading and cell-cycle progression. Mutation of the ORC1 BAH domain has been implicated in the aetiology of Meier–Gorlin syndrome (MGS)
3
,
4
, a form of primordial dwarfism
5
, and ORC1 depletion in zebrafish results in an MGS-like phenotype
4
. We find that wild-type human ORC1, but not ORC1–H4K20me2-binding mutants, rescues the growth retardation of
orc1
morphants. Moreover, zebrafish depleted of H4K20me2 have diminished body size, mirroring the phenotype of
orc1
morphants. Together, our results identify the BAH domain as a novel |
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ISSN: | 0028-0836 1476-4687 |
DOI: | 10.1038/nature10956 |