SMARCAL1 Resolves Replication Stress at ALT Telomeres

Cell Rep. 2016 Feb 9;14(5):1032-1040. doi: 10.1016/j.celrep.2016.01.011. Epub 2016 Jan 28.

Abstract

Cancer cells overcome replicative senescence by exploiting mechanisms of telomere elongation, a process often accomplished by reactivation of the enzyme telomerase. However, a subset of cancer cells lack telomerase activity and rely on the alternative lengthening of telomeres (ALT) pathway, a recombination-based mechanism of telomere elongation. Although the mechanisms regulating ALT are not fully defined, chronic replication stress at telomeres might prime these fragile regions for recombination. Here, we demonstrate that the replication stress response protein SMARCAL1 is a critical regulator of ALT activity. SMARCAL1 associates with ALT telomeres to resolve replication stress and ensure telomere stability. In the absence of SMARCAL1, persistently stalled replication forks at ALT telomeres deteriorate into DNA double-strand breaks promoting the formation of chromosome fusions. Our studies not only define a role for SMARCAL1 in ALT telomere maintenance, but also demonstrate that resolution of replication stress is a crucial step in the ALT mechanism.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cellular Senescence*
  • Chromosome Aberrations
  • DNA Breaks, Double-Stranded
  • DNA Helicases / metabolism*
  • Humans
  • Rad51 Recombinase / metabolism
  • Stress, Physiological*
  • Telomere / metabolism*
  • Telomere Homeostasis*

Substances

  • Rad51 Recombinase
  • SMARCAL1 protein, human
  • DNA Helicases