title: CHK2 kinase promotes pre-mRNA splicing via phosphorylating CDK11(p110).
abstract: Checkpoint kinase 2 (CHK2) kinase is a key mediator in many cellular responses to genotoxic stresses, including ionizing radiation (IR) and topoisomerase inhibitors. Upon IR, CHK2 is activated by ataxia telangiectasia mutated kinase and regulates the S-phase and G1-S checkpoints, apoptosis and DNA repair by phosphorylating downstream target proteins, such as p53 and Brca1. In addition, CHK2 is thought to be a multi-organ cancer susceptibility gene. In this study, we used a tandem affinity purification strategy to identify proteins that interact with CHK2 kinase. Cyclin-dependent kinase 11 (CDK11)(p110) kinase, implicated in pre-mRNA splicing and transcription, was identified as a CHK2-interacting protein. CHK2 kinase phosphorylated CDK11(p110) on serine 737 in vitro. Unexpectedly, CHK2 kinase constitutively phosphorylated CDK11(p110) in a DNA damage-independent manner. At a molecular level, CDK11(p110) phosphorylation was required for homodimerization without affecting its kinase activity. Overexpression of CHK2 promoted pre-mRNA splicing. Conversely, CHK2 depletion decreased endogenous splicing activity. Mutation of the phosphorylation site in CDK11(p110) to alanine abrogated its splicing-activating activity. These results provide the first evidence that CHK2 kinase promotes pre-mRNA splicing via phosphorylating CDK11(p110).
authors.affiliation: Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon, Republic of Korea.
authors.forename: H-H
authors.initials: HH
authors.lastname: Choi
authors.affiliation: Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon, Republic of Korea.
authors.forename: H-K
authors.initials: HK
authors.lastname: Choi
authors.affiliation: Center for Molecular Discovery, Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, USA.
authors.forename: S Y
authors.initials: SY
authors.lastname: Jung
authors.affiliation: Department of Genetics and Tumor Cell Biology, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: J
authors.initials: J
authors.lastname: Hyle
authors.affiliation: Center for Molecular Discovery, Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, USA.
authors.forename: B-J
authors.initials: BJ
authors.lastname: Kim
authors.affiliation: School of Life Science and Biotechnology, Sungkyunkwan University, Suwon, Republic of Korea.
authors.forename: K
authors.initials: K
authors.lastname: Yoon
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea.
authors.forename: E-J
authors.initials: EJ
authors.lastname: Cho
authors.affiliation: National Research Laboratory for Metabolic Checkpoint, Departments of Biomedical Sciences and Biochemistry and Molecular Biology, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: H-D
authors.initials: HD
authors.lastname: Youn
authors.affiliation: Department of Genetics and Tumor Cell Biology, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Lahti
authors.affiliation: Center for Molecular Discovery, Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, USA.
authors.forename: J
authors.initials: J
authors.lastname: Qin
authors.affiliation: Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon, Republic of Korea.
authors.forename: S-T
authors.initials: ST
authors.lastname: Kim
mesh_terms: D000595:Amino Acid Sequence; D064447:Checkpoint Kinase 2 / Q000737:chemistry / Q000502:physiology*; D018844:Cyclin-Dependent Kinases / Q000737:chemistry / Q000378:metabolism*; D004249:DNA Damage; D057809:HEK293 Cells; D019073:HT29 Cells; D006801:Humans; D010766:Phosphorylation; D025941:Protein Interaction Mapping; D055503:Protein Multimerization; D011499:Protein Processing, Post-Translational; D012322:RNA Precursors / Q000235:genetics* / Q000378:metabolism; D012326:RNA Splicing; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism
chemical_list: D012322:RNA Precursors; D012333:RNA, Messenger; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; C447612:CDK11a protein, human; D018844:Cyclin-Dependent Kinases