CGGBP1 phosphorylation constitutes a telomere-protection signal

Cell Cycle. 2014;13(1):96-105. doi: 10.4161/cc.26813. Epub 2013 Oct 23.

Abstract

The shelterin proteins are required for telomere integrity. Shelterin dysfunction can lead to initiation of unwarranted DNA damage and repair pathways at chromosomal termini. Interestingly, many shelterin accessory proteins are involved in DNA damage signaling and repair. We demonstrate here that in normal human fibroblasts, telomeric ends are protected by phosphorylation of CGG triplet repeat-binding protein 1 (CGGBP1) at serine 164 (S164). We show that serine 164 is a major phosphorylation site on CGGBP1 with important functions. We provide evidence that one of the kinases that can phosphorylate S164 CGGBP1 is ATR. Overexpression of S164A phospho-deficient CGGBP1 exerted a dominant-negative effect, causing telomeric dysfunction, accelerated telomere shortening, enhanced fusion of telomeres, and crisis. However, overexpression of wild-type or phospho-mimicking S164E CGGBP1 did not cause these effects. This telomere damage was associated with reduced binding of the shelterin protein POT1 to telomeric DNA. Our results suggest that CGGBP1 phosphorylation at S164 is a novel telomere protection signal, which can affect telomere-protective function of the shelterin complex.

Keywords: CGGBP1; DNA damage; POT1; Telomeres; telomere fusions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle Proteins / genetics
  • DNA Damage / genetics*
  • DNA-Binding Proteins / genetics*
  • Gene Expression Regulation
  • Humans
  • Phosphorylation
  • Serine / genetics*
  • Shelterin Complex
  • Signal Transduction / genetics
  • Telomere / genetics*
  • Telomere-Binding Proteins / genetics

Substances

  • CGGBP1 protein, human
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Shelterin Complex
  • Telomere-Binding Proteins
  • Serine