title: Phosphorylated Rad18 directs DNA polymerase η to sites of stalled replication.
abstract: The E3 ubiquitin ligase Rad18 guides DNA Polymerase eta (Polη) to sites of replication fork stalling and mono-ubiquitinates proliferating cell nuclear antigen (PCNA) to facilitate binding of Y family trans-lesion synthesis (TLS) DNA polymerases during TLS. However, it is unclear exactly how Rad18 is regulated in response to DNA damage and how Rad18 activity is coordinated with progression through different phases of the cell cycle. Here we identify Rad18 as a novel substrate of the essential protein kinase Cdc7 (also termed Dbf4/Drf1-dependent Cdc7 kinase [DDK]). A serine cluster in the Polη-binding motif of Rad 18 is phosphorylated by DDK. Efficient association of Rad18 with Polη is dependent on DDK and is necessary for redistribution of Polη to sites of replication fork stalling. This is the first demonstration of Rad18 regulation by direct phosphorylation and provides a novel mechanism for integration of S phase progression with postreplication DNA repair to maintain genome stability.
authors.affiliation: Department of Genetics and Genomics and 2 Center for Human Genetics, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Tovah A
authors.initials: TA
authors.lastname: Day
authors.forename: Komariah
authors.initials: K
authors.lastname: Palle
authors.forename: Laura R
authors.initials: LR
authors.lastname: Barkley
authors.forename: Naoko
authors.initials: N
authors.lastname: Kakusho
authors.forename: Ying
authors.initials: Y
authors.lastname: Zou
authors.forename: Satoshi
authors.initials: S
authors.lastname: Tateishi
authors.forename: Alain
authors.initials: A
authors.lastname: Verreault
authors.forename: Hisao
authors.initials: H
authors.lastname: Masai
authors.forename: Cyrus
authors.initials: C
authors.lastname: Vaziri
mesh_terms: D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004259:DNA-Directed DNA Polymerase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008856:Microscopy, Fluorescence; D010766:Phosphorylation; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D016196:S Phase; D014162:Transfection; D044767:Ubiquitin-Protein Ligases; D000099270:Y-Family DNA Polymerases
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D004259:DNA-Directed DNA Polymerase; D018809:Proliferating Cell Nuclear Antigen; D017346:Protein Serine-Threonine Kinases; D044767:Ubiquitin-Protein Ligases; C485954:RAD18 protein, human; C068619:CDC7 protein, human; C112338:Rad30 protein; D000099270:Y-Family DNA Polymerases