Dbf4-dependent kinase finetunes Ino80 function at chromosome replication origins

TL;DR

This study reveals that the Dbf4-Dependent Kinase (DDK) regulates the INO80 chromatin remodeler, improving replication and genome stability.

Contribution

The study identifies INO80 as a novel DDK target, showing its role in replication origin chromatin architecture.

Findings

DDK phosphorylates the Arp8 subunit of INO80, stabilizing the complex.

Phosphorylated INO80 improves nucleosome spacing and replication efficiency.

DDK regulates chromatin remodeling to support replication and genome stability.

Abstract

The highly conserved Dbf4-Dependent Kinase (DDK) plays a pivotal role during S phase. It phosphorylates the replicative helicase (minichromosome maintenance, MCM complex), which leads to the initiation of replication. However, few other targets, besides the MCM complex, are known, leaving DDK an understudied kinase. Here, we determine the nuclear DDK-dependent phosphoproteome by a two-pronged mass spectrometry approach. Among ~ 400 DDK-dependent phosphorylation targets, we find the Arp8 subunit of the INO80 chromatin remodeling complex. Arp8 phosphorylation stabilises INO80’s complex integrity, finetunes its nucleosome spacing at replication origins, stimulates replication and improves the replication stress response. Taken together, we report the regulation of a chromatin remodeler with nucleosome-spacing activity by the cell-cycle machinery. DDK not only regulates the core replication machinery but also regulates a factor that generates replication-conducive chromatin architecture at replication origins.

DDK kinase not only acts on the core replication machinery but also regulates the INO80 chromatin remodeler, shaping chromatin at replication origins and supporting replication and genome stability.

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