The Werner syndrome exonuclease facilitates DNA degradation and high fidelity DNA polymerization by human DNA polymerase δ

Abstract:

DNA Polymerase δ (Pol δ) and the Werner syndrome (WS) protein, WRN are involved in maintaining cellular genomic stability. Pol δ synthesizes the lagging strand during replication of genomic DNA, and also functions in the synthesis steps of DNA repair and recombination. WRN is a member of the RecQ helicase family, loss of which results in the premature ageing and cancer-prone disorder, Werner syndrome. Both Pol δ and WRN encode 3'→5' DNA exonuclease activities. Pol δ exonuclease removes 3'-terminal mismatched nucleotides incorporated during replication to ensure high fidelity DNA synthesis. WRN exonuclease degrades DNA containing alternate secondary structures to prevent formation, and enable resolution of stalled replication forks. We now observe that similarly to WRN, Pol δ degrades alternate DNA structures including bubbles, four-way junctions, and D-loops. Moreover, WRN and Pol δ form a complex with enhanced ability to hydrolyze these structures. We also present evidence that WRN can proof-read for Pol δ; WRN excises 3'-terminal mismatches to enable primer extension by Pol δ. Consistent with our in vitro observations, we show that WRN contributes to the maintenance of DNA synthesis fidelity in vivo. Cells expressing limiting amounts (~10% of normal) of WRN have elevated mutation frequencies compared to wild-type cells. Together, our data highlight the importance of WRN exonuclease activity and its co-operativity with Pol δ in preserving genome stability, which is compromised by the loss of WRN in WS.

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