Replication licensing regulated by a short linear motif within an intrinsically disordered region of origin recognition complex

Yue Wu, Qiongdan Zhang, Yuhan Lin, Wai Hei Lam and Yuanliang Zhai ()
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Yue Wu: The University of Hong Kong
Qiongdan Zhang: The University of Hong Kong
Yuhan Lin: The University of Hong Kong
Wai Hei Lam: The University of Hong Kong
Yuanliang Zhai: The University of Hong Kong

Nature Communications, 2024, vol. 15, issue 1, 1-11

Abstract: Abstract In eukaryotes, the origin recognition complex (ORC) faciliates the assembly of pre-replicative complex (pre-RC) at origin DNA for replication licensing. Here we show that the N-terminal intrinsically disordered region (IDR) of the yeast Orc2 subunit is crucial for this process. Removing a segment (residues 176-200) from Orc2-IDR or mutating a key isoleucine (194) significantly inhibits replication initiation across the genome. These Orc2-IDR mutants are capable of assembling the ORC-Cdc6-Cdt1-Mcm2-7 intermediate, which exhibits impaired ATP hydrolysis and fails to be convered into the subsequent Mcm2-7-ORC complex and pre-RC. These defects can be partially rescued by the Orc2-IDR peptide. Moreover, the phosphorylation of this Orc2-IDR region by S cyclin-dependent kinase blocks its binding to Mcm2-7 complex, causing a defective pre-RC assembly. Our findings provide important insights into the multifaceted roles of ORC in supporting origin licensing during the G1 phase and its regulation to restrict origin firing within the S phase.

Date: 2024
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DOI: 10.1038/s41467-024-52408-0

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