Abstract
Helicases are enzymes that use the energy derived from ATP hydrolysis to catalyze the unwinding of DNA or RNA. The RecQ family of helicases is conserved through evolution from prokaryotes to higher eukaryotes and plays important roles in various DNA repair pathways, contributing to the maintenance of genome integrity. Despite their roles as general tumor suppressors, there is now considerable interest in exploiting RecQ helicases as synthetic lethal targets for the development of new cancer therapeutics. In this review, we summarize the latest developments in the structural and mechanistic study of RecQ helicases and discuss their roles in various DNA repair pathways. Finally, we consider the potential to exploit RecQ helicases as therapeutic targets and review the recent progress towards the development of small molecules targeting RecQ helicases as cancer therapeutics.
Highlights
The RecQ family of helicases unwind DNA in a 3 to 5 direction and contribute to the maintenance of genome integrity by playing important roles in multiple DNA repair pathways
In the initial stages of the homologous recombination (HR) pathway, Bloom’s syndrome helicase (BLM) is capable of interacting with EXO1 [4] and DNA2 [5,6] and promoting long range end resection, whilst in the latter stages it is capable, along with other RecQ family members of Holiday junction (HJ) branch migration [7,8], and in a complex with Topoisomerase Iiα and RMI1/2 plays a key role in the dissolution of double HJ [9]
Whilst Werner syndrome helicase (WRN) is not a core component of the Canonical nonhomologous end joining (c-NHEJ) pathway it appears to be important for efficient double strand break repair [17], and is involved in pathway choice promoting classical NHEJ over alternate pathways via shielding DNA ends from resection [19]
Summary
The RecQ family of helicases is conserved through evolution from prokaryotes to higher eukaryotes and plays important roles in various DNA repair pathways, contributing to the maintenance of genome integrity. Despite their roles as general tumor suppressors, there is considerable interest in exploiting RecQ helicases as synthetic lethal targets for the development of new cancer therapeutics. We summarize the latest developments in the structural and mechanistic study of RecQ helicases and discuss their roles in various DNA repair pathways. We consider the potential to exploit RecQ helicases as therapeutic targets and review the recent progress towards the development of small molecules targeting RecQ helicases as cancer therapeutics
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