title: The DNA repair component Metnase regulates Chk1 stability.
abstract: Chk1 both arrests replication forks and enhances repair of DNA damage by phosphorylation of downstream effectors. Metnase (also termed SETMAR) is a SET histone methylase and transposase nuclease protein that promotes both DNA double strand break (DSB) repair and re-start of stalled replication forks. We previously found that Chk1 phosphorylation of Metnase on S495 enhanced its DNA DSB repair activity but decreased its ability to re-start stalled replication forks. Here we show that phosphorylated Metnase feeds back to increase the half-life of Chk1. Chk1 half-life is regulated by DDB1 targeting it to Cul4A for ubiquitination and destruction. Metnase decreases Chk1 interaction with DDB1, and decreases Chk1 ubiquitination. These data define a novel pathway for Chk1 regulation, whereby a target of Chk1, Metnase, feeds back to amplify Chk1 stability, and therefore enhance replication fork arrest.
authors.affiliation: Department of Medicine, University of Florida College of Medicine, 1600 Archer Rd SW, Gainesville, FL 32610, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Williamson
authors.affiliation: Department of Medicine, University of Florida College of Medicine, 1600 Archer Rd SW, Gainesville, FL 32610, USA.
authors.forename: Yuehan
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Medicine, University of Florida College of Medicine, 1600 Archer Rd SW, Gainesville, FL 32610, USA.
authors.forename: Sudha
authors.initials: S
authors.lastname: Singh
authors.affiliation: Department of Medicine, University of Florida College of Medicine, 1600 Archer Rd SW, Gainesville, FL 32610, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Byrne
authors.affiliation: Department of Medicine, University of Florida College of Medicine, 1600 Archer Rd SW, Gainesville, FL 32610, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Wray
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Suk-Hee
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO 80523, USA.
authors.forename: Jac A
authors.initials: JA
authors.lastname: Nickoloff
authors.affiliation: Department of Medicine, University of Florida College of Medicine, 1600 Archer Rd SW, Gainesville, FL 32610, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Hromas
keywords: Cell cycle; Chk1; DNA repair; Ubiquitination