Promotion of homology-directed DNA repair by polyamines

Chih-Ying Lee,Sung-Jan Lin,Min-Yu Ko,Wen-Yen Huang,Geen-Dong Chang,Guan-Chin Su,Hsin-Yi Yeh,Peter Chi

doi:10.1038/s41467-018-08011-1

Abstract

Polyamines, often elevated in cancer cells, have been shown to promote cell growth and proliferation. Whether polyamines regulate other cell functions remains unclear. Here, we explore whether and how polyamines affect genome integrity. When DNA double-strand break (DSB) is induced in hair follicles by ionizing radiation, reduction of cellular polyamines augments dystrophic changes with delayed regeneration. Mechanistically, polyamines facilitate homologous recombination-mediated DSB repair without affecting repair via non-homologous DNA end-joining and single-strand DNA annealing. Biochemical reconstitution and functional analyses demonstrate that polyamines enhance the DNA strand exchange activity of RAD51 recombinase. The effect of polyamines on RAD51 stems from their ability to enhance the capture of homologous duplex DNA and synaptic complex formation by the RAD51-ssDNA nucleoprotein filament. Our work demonstrates a novel function of polyamines in the maintenance of genome integrity via homology-directed DNA repair.

Highlights

Polyamines, often elevated in cancer cells, have been shown to promote cell growth and proliferation
We show that polyamines upregulate homologous recombination (HR) but have little or no impact on nonhomologous DNA end-joining (NHEJ) and single-strand DNA annealing (SSA)
We first tested the physiological relevance of polyamines in double-strand break (DSB) repair in hair follicles after ionizing radiation (IR) injury

Summary

Introduction

Polyamines, often elevated in cancer cells, have been shown to promote cell growth and proliferation. Polyamines facilitate homologous recombination-mediated DSB repair without affecting repair via nonhomologous DNA end-joining and single-strand DNA annealing. Our work demonstrates a novel function of polyamines in the maintenance of genome integrity via homology-directed DNA repair. Several studies have demonstrated that depletion of polyamines sensitizes cells to genotoxic substances, including ionizing radiation (IR), ultraviolet (UV), and etoposide[6,7,8], that can induce DNA double-strand breaks (DSBs). We show that polyamines upregulate homologous recombination (HR) but have little or no impact on nonhomologous DNA end-joining (NHEJ) and single-strand DNA annealing (SSA). Polyamines promote RAD51mediated DNA strand exchange by facilitating the capture of duplex DNA by the RAD51 presynaptic filament. Our study furnishes insights into the role of polyamines in genome maintenance via homology-directed DNA repair

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Results

Conclusion