HnRNP A1 phosphorylated by VRK1 stimulates telomerase and its binding to telomeric DNA sequence

Nucleic Acids Res. 2012 Sep 1;40(17):8499-518. doi: 10.1093/nar/gks634. Epub 2012 Jun 26.

Abstract

The telomere integrity is maintained via replication machinery, telomere associated proteins and telomerase. Many telomere associated proteins are regulated in a cell cycle-dependent manner. Heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1), a single-stranded oligonucleotide binding protein, is thought to play a pivotal role in telomere maintenance. Here, we identified hnRNP A1 as a novel substrate for vaccinia-related kinase 1 (VRK1), a cell cycle regulating kinase. Phosphorylation by VRK1 potentiates the binding of hnRNP A1 to telomeric ssDNA and telomerase RNA in vitro and enhances its function for telomerase reaction. VRK1 deficiency induces a shortening of telomeres with an abnormal telomere arrangement and activation of DNA-damage signaling in mouse male germ cells. Together, our data suggest that VRK1 is required for telomere maintenance via phosphorylation of hnRNP A1, which regulates proteins associated with the telomere and telomerase RNA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Binding Sites
  • Cell Cycle / genetics
  • DNA, Single-Stranded / chemistry
  • DNA, Single-Stranded / metabolism*
  • HeLa Cells
  • Heterogeneous Nuclear Ribonucleoprotein A1
  • Heterogeneous-Nuclear Ribonucleoprotein Group A-B / chemistry
  • Heterogeneous-Nuclear Ribonucleoprotein Group A-B / metabolism*
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Male
  • Mice
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / deficiency
  • Protein-Serine-Threonine Kinases / metabolism*
  • RNA / metabolism
  • Spermatogonia / metabolism
  • Telomerase / metabolism*
  • Telomere / chemistry
  • Telomere / metabolism*
  • Telomere Homeostasis*

Substances

  • DNA, Single-Stranded
  • Heterogeneous Nuclear Ribonucleoprotein A1
  • Heterogeneous-Nuclear Ribonucleoprotein Group A-B
  • Hnrnpa1 protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • hnRNPA1 protein, human
  • telomerase RNA
  • RNA
  • Protein-Serine-Threonine Kinases
  • VRK1 protein, human
  • Vrk1 protein, mouse
  • Telomerase