Nature Communications (Sep 2024)

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,
  • Yuanliang Zhai

DOI
https://doi.org/10.1038/s41467-024-52408-0
Journal volume & issue
Vol. 15, no. 1
pp. 1 – 11

Abstract

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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.