R152C DNA Pol β mutation impairs base excision repair and induces cellular transformation.

Ting Zhou,Zhigang Hu,Xuping Wu,Yan Cao,Zhigang Guo,Binghui Shen,Lingfeng He,Feiyan Pan,Haoyan Chen,Hongfang Sun,Xiaolong Zhou,Ying Han,Jing Zhao

doi:10.18632/oncotarget.6849

Abstract

DNA polymerase β (Pol β) is a key enzyme in DNA base excision repair (BER), a pathway that maintains genome integrity and stability. Pol β mutations have been detected in various types of cancers, suggesting a possible linkage between Pol β mutations and cancer. However, it is not clear whether and how Pol β mutations cause cancer onset and progression. In the current work, we show that a substitution mutation, R152C, impairs Pol β polymerase activity and BER efficiency. Cells harboring Pol β R152C are sensitive to the DNA damaging agents methyl methanesulfonate (MMS) and H2O2. Moreover, the mutant cells display a high frequency of chromatid breakages and aneuploidy and also form foci. Taken together, our data indicate that Pol β R152C can drive cellular transformation.

Highlights

Genomic DNA is constantly exposed to endogenous and exogenous insults, which cause DNA damage
In LP-Base excision repair (BER), polymerase β (Pol β) performs strand displacement synthesis, generating a 2-10 nt short DNA flap, which is removed by flap endonuclease 1 (FEN1) [16,17,18,19,20]
Cells harboring Pol β R152C accumulated more genomic DNA damage in response to DNA damaging agents, which induced www.impactjournals.com/oncotarget aneuploidy and a higher cellular transformation efficiency. These results suggest that the R152C mutation reduces Pol β biochemical activity, resulting in defective BER, which might contribute to genome instability and cancer development

Summary

INTRODUCTION

Genomic DNA is constantly exposed to endogenous and exogenous insults, which cause DNA damage. Base excision repair (BER), which removes DNA base damage caused by endogenous and exogenous agents, is a major repair pathway in eukaryotic cells [3,4,5,6]. Pol β interacts with many other proteins including APE1, PCNA and FEN1 [26, 27] These interactions can recruit downstream factors to the DNA repair site, reciprocally stimulate enzyme activities, and coordinate the highly ordered chemical reactions of BER. Www.impactjournals.com/oncotarget aneuploidy and a higher cellular transformation efficiency These results suggest that the R152C mutation reduces Pol β biochemical activity, resulting in defective BER, which might contribute to genome instability and cancer development

RESULTS

MATERIALS AND METHODS

CONFLICTS OF INTEREST