Nucleosomal embedding reshapes the dynamics of abasic sites

Emmanuelle Bignon,Natacha Gillet,Elise Dumont,Tao Jiang,Christophe Morell,Victor E P Claerbout

doi:10.1038/s41598-020-73997-y

Abstract

Apurinic/apyrimidinic (AP) sites are the most common DNA lesions, which benefit from a most efficient repair by the base excision pathway. The impact of losing a nucleobase on the conformation and dynamics of B-DNA is well characterized. Yet AP sites seem to present an entirely different chemistry in nucleosomal DNA, with lifetimes reduced up to 100-fold, and the much increased formation of covalent DNA-protein cross-links leading to strand breaks, refractory to repair. We report microsecond range, all-atom molecular dynamics simulations that capture the conformational dynamics of AP sites and their tetrahydrofuran analogs at two symmetrical positions within a nucleosome core particle, starting from a recent crystal structure. Different behaviours between the deoxyribo-based and tetrahydrofuran-type abasic sites are evidenced. The two solvent-exposed lesion sites present contrasted extrahelicities, revealing the crucial role of the position of a defect around the histone core. Our all-atom simulations also identify and quantify the frequency of several spontaneous, non-covalent interactions between AP and positively-charged residues from the histones H2A and H2B tails that prefigure DNA-protein cross-links. Such an in silico mapping of DNA-protein cross-links gives important insights for further experimental studies involving mutagenesis and truncation of histone tails to unravel mechanisms of DPCs formation.

Highlights

Apurinic/apyrimidinic (AP) sites are the most common DNA lesions, which benefit from a most efficient repair by the base excision pathway
Apurinic/apyrimidinic (AP) sites are the most frequent spontaneous DNA lesions, amounting to 5000–10,000 lesions per day per mammal cell[1,2]. They are generated by hydrolysis of the N-glycosylic bond between a nucleobase and a d eoxyribose[3], spontaneously or as intermediates in the excision repair of damaged bases. Their repair by dedicated enzymes turns out to be most efficient by base excision repair (BER) and nucleotide excision repair (NER)[4]
In direct line with the recent experimental X-ray investigation[13], our simulations allow us to test at the microsecond range the stability on the so-called “inchworm” conformation of tetrahydrofuran-type abasic sites

Summary

Introduction

Apurinic/apyrimidinic (AP) sites are the most common DNA lesions, which benefit from a most efficient repair by the base excision pathway. Our all-atom simulations identify and quantify the frequency of several spontaneous, non-covalent interactions between AP and positively-charged residues from the histones H2A and H2B tails that prefigure DNA-protein cross-links. Such an in silico mapping of DNAprotein cross-links gives important insights for further experimental studies involving mutagenesis and truncation of histone tails to unravel mechanisms of DPCs formation. Apurinic/apyrimidinic (AP) sites are the most frequent spontaneous DNA lesions, amounting to 5000–10,000 lesions per day per mammal cell[1,2] They are generated by hydrolysis of the N-glycosylic bond between a nucleobase and a d eoxyribose[3], spontaneously or as intermediates in the excision repair of damaged bases. A different structural behavior exhibited by AP and THF sites within the NCP is detailed, and interactions with residues of the H2A tail are mapped

Methods

Results

Conclusion