title: GINS complex protein Sld5 recruits SIK1 to activate MCM helicase during DNA replication.
abstract: In eukaryotes, proper loading and activation of MCM helicase at chromosomal origins plays a central role in DNA replication. Activation of MCM helicase requires its association with CDC45-GINS complex, but the mechanism of how this complex activates MCM helicase is poorly understood. Here we identified SIK1 (salt-inducible kinase 1), an AMPK related protein kinase, as a molecular link that connects GINS complex with MCM helicase activity. We demonstrated that Sld5 a component of GINS complex interacts with SIK1 and recruits it to the sites of DNA replication at the onset of S phase. Depletion of SIK1 leads to defective DNA replication. Further, we showed that SIK1 phosphorylates MCM2 at five conserved residues at its N-terminus, which is essential for the activation of MCM helicase. Collectively, our results suggest SIK1 as a novel integral component of CMG replicative helicase during eukaryotic DNA replication.
authors: Laboratory of Cell Death & Cell Survival, Centre for DNA Fingerprinting and Diagnostics (CDFD), Nampally, Hyderabad 500001, India.
authors: Kiranmai
authors: K
authors: Joshi
authors: Laboratory of Cell Death & Cell Survival, Centre for DNA Fingerprinting and Diagnostics (CDFD), Nampally, Hyderabad 500001, India; Manipal University, Manipal 576104, India.
authors: Varun Jayeshkumar
authors: VJ
authors: Shah
authors: Laboratory of Cell Death & Cell Survival, Centre for DNA Fingerprinting and Diagnostics (CDFD), Nampally, Hyderabad 500001, India. Electronic address: msreddy@cdfd.org.in.
authors: Subbareddy
authors: S
authors: Maddika
mesh_terms: D000595:Amino Acid Sequence; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism*; D004261:DNA Replication; D016193:G1 Phase; D006367:HeLa Cells; D006801:Humans; D064111:Minichromosome Maintenance Complex Component 2 / Q000737:chemistry / Q000378:metabolism*; D008954:Models, Biological; D046912:Multiprotein Complexes / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D016196:S Phase
chemical_list: D002868:Chromosomal Proteins, Non-Histone; C521091:GINS4 protein, human; D046912:Multiprotein Complexes; D017346:Protein Serine-Threonine Kinases; C509080:SIK1 protein, human; C084859:MCM2 protein, human; D064111:Minichromosome Maintenance Complex Component 2
keywords: Gins; MCM helicase; Replication; SIK1; Sld5