title: DNA-PKcs phosphorylates hnRNP-A1 to facilitate the RPA-to-POT1 switch and telomere capping after replication.
abstract: The heterogeneous nuclear ribonucleoprotein A1 (hnRNP-A1) has been implicated in telomere protection and telomerase activation. Recent evidence has further demonstrated that hnRNP-A1 plays a crucial role in maintaining newly replicated telomeric 3' overhangs and facilitating the switch from replication protein A (RPA) to protection of telomeres 1 (POT1). The role of hnRNP-A1 in telomere protection also involves DNA-dependent protein kinase catalytic subunit (DNA-PKcs), although the detailed regulation mechanism has not been clear. Here we report that hnRNP-A1 is phosphorylated by DNA-PKcs during the G2 and M phases and that DNA-PK-dependent hnRNP-A1 phosphorylation promotes the RPA-to-POT1 switch on telomeric single-stranded 3' overhangs. Consequently, in cells lacking hnRNP-A1 or DNA-PKcs-dependent hnRNP-A1 phosphorylation, impairment of the RPA-to-POT1 switch results in DNA damage response at telomeres during mitosis as well as induction of fragile telomeres. Taken together, our results indicate that DNA-PKcs-dependent hnRNP-A1 phosphorylation is critical for capping of the newly replicated telomeres and prevention of telomeric aberrations.
authors.affiliation: Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA Cancer Center, Daping Hospital, Third Military Medical University, Chongqing 400042, China.
authors.forename: Jiangdong
authors.initials: J
authors.lastname: Sui
authors.affiliation: Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Yu-Fen
authors.initials: YF
authors.lastname: Lin
authors.affiliation: Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Kangling
authors.initials: K
authors.lastname: Xu
authors.affiliation: Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Kyung-Jong
authors.initials: KJ
authors.lastname: Lee
authors.affiliation: Cancer Center, Daping Hospital, Third Military Medical University, Chongqing 400042, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA benjamin.chen@utsouthwestern.edu.
authors.forename: Benjamin P C
authors.initials: BP
authors.lastname: Chen
mesh_terms: D045744:Cell Line, Tumor; D004260:DNA Repair; D004261:DNA Replication; D004277:DNA, Single-Stranded / Q000378:metabolism; D051747:DNA-Activated Protein Kinase / Q000378:metabolism*; D000076245:Heterogeneous Nuclear Ribonucleoprotein A1; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000378:metabolism*; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation; D051716:Replication Protein A / Q000378:metabolism*; D000089804:Shelterin Complex; D016615:Telomere / Q000378:metabolism*; D034501:Telomere-Binding Proteins / Q000378:metabolism*
chemical_list: D004277:DNA, Single-Stranded; D000076245:Heterogeneous Nuclear Ribonucleoprotein A1; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; D009687:Nuclear Proteins; C440849:POT1 protein, human; D051716:Replication Protein A; D000089804:Shelterin Complex; D034501:Telomere-Binding Proteins; C000619656:hnRNPA1 protein, human; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human