RECQL5 Suppresses Oncogenic JAK2-Induced Replication Stress and Genomic Instability.

Abstract

JAK2V617F is the most common oncogenic lesion in patients with myeloproliferative neoplasms (MPNs). Despite the ability of JAK2V617F to instigate DNA damage in vitro, MPNs are nevertheless characterized by genomic stability. In this study, we address this paradox by identifying the DNA helicase RECQL5 as a suppressor of genomic instability in MPNs. We report increased RECQL5 expression in JAK2V617F-expressing cells and demonstrate that RECQL5 is required to counteract JAK2V617F-induced replication stress. Moreover, RECQL5 depletion sensitizes JAK2V617F mutant cells to hydroxyurea (HU), a pharmacological inducer of replication stress and the most common treatment for MPNs. Using single-fiber chromosome combing, we show that RECQL5 depletion in JAK2V617F mutant cells impairs replication dynamics following HU treatment, resulting in increased double-stranded breaks and apoptosis. Cumulatively, these findings identify RECQL5 as a critical regulator of genome stability in MPNs and demonstrate that replication stress-associated cytotoxicity can be amplified specifically in JAK2V617F mutant cells through RECQL5-targeted synthetic lethality.

• Authors: Edwin Chen, Jong Sook Ahn, David B Sykes, Lawrence J Breyfogle, Anna L Godfrey, Jyoti Nangalia, Amy Ko, Daniel J DeAngelo, Anthony R Green, Ann Mullally
• Journal: Cell reports (Cell Rep) Vol. 13 Issue 11 Pg. 2345-2352 (Dec 22 2015) ISSN: 2211-1247 [Electronic] United States
• PMID: 26686625 (Publication Type: Journal Article)
• Copyright: Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Furans
• PI103
• Phosphoinositide-3 Kinase Inhibitors
• Pyridines
• Pyrimidines
• RECQL5 protein, human
• RNA, Small Interfering
• JAK2 protein, human
• Janus Kinase 2
• RecQ Helicases
• Hydroxyurea

Topics

• Animals
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Survival (drug effects)
• DNA Breaks, Double-Stranded (drug effects)
• DNA Replication (drug effects)
• Furans (pharmacology)
• Gene Knock-In Techniques
• Genomic Instability (drug effects)
• Humans
• Hydroxyurea (toxicity)
• Janus Kinase 2 (antagonists & inhibitors, genetics, metabolism)
• Mice
• Mice, Inbred C57BL
• Mutagenesis, Site-Directed
• Neoplasms (metabolism, pathology)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Pyridines (pharmacology)
• Pyrimidines (pharmacology)
• RNA Interference
• RNA, Small Interfering (metabolism)
• RecQ Helicases (genetics, metabolism)
• Signal Transduction (drug effects)