Targeted inhibition of WRN helicase, replication stress and cancer

Natalie Orlovetskie, Raphael Serruya, Ghada Abboud-Jarrous*, Nayef Jarrous

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

14 Scopus citations

Abstract

WRN helicase has several roles in genome maintenance, such as replication, base excision repair, recombination, DNA damage response and transcription. These processes are often found upregulated in human cancers, many of which display increased levels of WRN. Therefore, directed inhibition of this RecQ helicase could be beneficial to selective cancer therapy. Inhibition of WRN is feasible by the use of small-molecule inhibitors or application of RNA interference and EGS/RNase P targeting systems. Remarkably, helicase depletion leads to a severe reduction in cell viability due to mitotic catastrophe, which is triggered by replication stress induced by DNA repair failure and fork progression arrest. Moreover, we present new evidence that WRN depletion results in early changes of RNA polymerase III and RNase P activities, thereby implicating chromatin-associated tRNA enzymes in WRN-related stress response. Combined with the recently discovered roles of RecQ helicases in cancer, current data support the targeting prospect of these genome guardians, as a means of developing clinical phases aimed at diminishing adaptive resistance to present targeted therapies.

Original languageAmerican English
Pages (from-to)42-48
Number of pages7
JournalBiochimica et Biophysica Acta - Reviews on Cancer
Volume1867
Issue number1
DOIs
StatePublished - 1 Jan 2017

Bibliographical note

Publisher Copyright:
© 2016

Keywords

  • DNA repair
  • EGS
  • RNase P
  • Replication stress
  • Selective cancer therapy
  • WRN helicase

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