- PDB-8siu: Origin Recognition Complex Associated (ORCA) protein bound to Orc2 -
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Basic information
Entry
Database: PDB / ID: 8siu
Title
Origin Recognition Complex Associated (ORCA) protein bound to Orc2
Components
Leucine-rich repeat and WD repeat-containing protein 1
Origin recognition complex subunit 2
Keywords
PROTEIN BINDING / chromatin binding / ORC binding
Function / homology
Function and homology information
Activation of ATR in response to replication stress / Assembly of the ORC complex at the origin of replication / CDC6 association with the ORC:origin complex / Activation of the pre-replicative complex / Orc1 removal from chromatin / origin recognition complex / establishment of protein localization to chromatin / nuclear origin of replication recognition complex / inner kinetochore / methyl-CpG binding ...Activation of ATR in response to replication stress / Assembly of the ORC complex at the origin of replication / CDC6 association with the ORC:origin complex / Activation of the pre-replicative complex / Orc1 removal from chromatin / origin recognition complex / establishment of protein localization to chromatin / nuclear origin of replication recognition complex / inner kinetochore / methyl-CpG binding / DNA replication origin binding / DNA replication initiation / heterochromatin / pericentric heterochromatin / methylated histone binding / kinetochore / chromatin organization / DNA replication / chromosome, telomeric region / centrosome / chromatin binding / chromatin / nucleolus / nucleoplasm / nucleus / cytoplasm Similarity search - Function
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
5R01GM141313
United States
European Research Council (ERC)
ERC-STG-757909
European Union
Citation
Journal: EMBO J / Year: 2023 Title: A dual role for the chromatin reader ORCA/LRWD1 in targeting the origin recognition complex to chromatin. Authors: Sumon Sahu / Babatunde E Ekundayo / Ashish Kumar / Franziska Bleichert / Abstract: Eukaryotic cells use chromatin marks to regulate the initiation of DNA replication. The origin recognition complex (ORC)-associated protein ORCA plays a critical role in heterochromatin replication ...Eukaryotic cells use chromatin marks to regulate the initiation of DNA replication. The origin recognition complex (ORC)-associated protein ORCA plays a critical role in heterochromatin replication in mammalian cells by recruiting the initiator ORC, but the underlying mechanisms remain unclear. Here, we report crystal and cryo-electron microscopy structures of ORCA in complex with ORC's Orc2 subunit and nucleosomes, establishing that ORCA orchestrates ternary complex assembly by simultaneously recognizing a highly conserved peptide sequence in Orc2, nucleosomal DNA, and repressive histone trimethylation marks through an aromatic cage. Unexpectedly, binding of ORCA to nucleosomes prevents chromatin array compaction in a manner that relies on H4K20 trimethylation, a histone modification critical for heterochromatin replication. We further show that ORCA is necessary and sufficient to specifically recruit ORC into chromatin condensates marked by H4K20 trimethylation, providing a paradigm for studying replication initiation in specific chromatin contexts. Collectively, our findings support a model in which ORCA not only serves as a platform for ORC recruitment to nucleosomes bearing specific histone marks but also helps establish a local chromatin environment conducive to subsequent MCM2-7 loading.
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