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Replication licensing regulated by an intrinsically disordered region of origin recognition complex

ABSTRACT: Replication licensing regulated by an intrinsically disordered region of origin recognition complex

PROVIDER: PRJNA1093011 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR28491780_1.fastq.gz	Fastqsanger.gz
	SRR28491780_2.fastq.gz	Fastqsanger.gz
	SRR28491781_1.fastq.gz	Fastqsanger.gz
	SRR28491781_2.fastq.gz	Fastqsanger.gz
	SRR28491782_1.fastq.gz	Fastqsanger.gz

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Replication licensing regulated by an intrinsically disordered region of origin recognition complex

Project description:In eukaryotes, the hetero-hexameric origin recognition complex (ORC) is responsible for assembling Mcm2-7 complex into a head-to-head double hexamer (DH), forming pre-replicative complex (pre-RC) that licenses origin DNA for replication initiation. This process is tightly controlled throughout the cell cycle to ensure accurate duplication of the genome. Here we show that the N-terminal intrinsically disordered region (IDR) of the yeast Orc2 subunit plays a critical role in promoting pre-RC assembly. We found that removing a short segment (residues 175-200) from Orc2-IDR or mutating a key isoleucine (194) in this region significantly inhibits replication initiation across the genome and causes cell death. Although the Orc2-IDR mutants can still assemble the ORC-Cdc6-Cdt1-Mcm2-7 (OCCM) intermediate on DNA, the assembled mutant OCCM exhibits impaired ATP hydrolysis, preventing its conversion into Mcm2-7-ORC (MO) complex and subsequent DH formation. Interestingly, our in vitro assays showed that adding the Orc2-IDR peptide in the pre-RC reactions can rescue this defect. Furthermore, phosphorylation of this Orc2-IDR motif by S-cyclin dependent kinase (S-CDK) blocks its binding to Mcm2, leading to defective pre-RC assembly. Our findings provide crucial mechanistic insights into the multifaceted roles of ORC in modulating MCM loading to support origin licensing during the G1 phase and its regulation to restrict origin firing within the S phase.

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Multisite phosphorylation of intrinsically disordered region of DVL

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Project description:When WNT binds to its receptor Frizzled (FZD) to activate the signaling, Dishevelled (DVL), the central component of Wnt signaling, is phosphorylated by redundant Casein kinase 1 (CK1) isoforms ε or δ, to transduce the signal downstream. Although the basic principles of Wnt signal transduction are known, the mechanistic aspects of DVL phosphorylation remain elusive. Here we identify Wnt-dependent multisite phosphorylation of a large and conserved serine/threonine (S/T) cluster within intrinsically disordered region (IDR), located between the PDZ and DEP domains. The detailed analysis of the phosphorylation and its effect on the flanking domains was performed with the construct containing both domains PDZ and DEP flanking the IDR (hDVL3 PDZ-DEP, aa 243-496).

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