HSSB1 (NABP2/OBFC2B) is regulated by oxidative stress.

Nicolas Paquet,Christine Touma,Nicholas W Ashton,Mark N Adams,Vincent Leong,Derek J Richard,Liza Cubeddu,Roland Gamsjaeger,Emma Bolderson,Sam Beard,Catherine H Botting,Kenneth J O’Byrne

doi:10.1038/srep27446

Abstract

The maintenance of genome stability is an essential cellular process to prevent the development of diseases including cancer. hSSB1 (NABP2/ OBFC2A) is a critical component of the DNA damage response where it participates in the repair of double-strand DNA breaks and in base excision repair of oxidized guanine residues (8-oxoguanine) by aiding the localization of the human 8-oxoguanine glycosylase (hOGG1) to damaged DNA. Here we demonstrate that following oxidative stress, hSSB1 is stabilized as an oligomer which is required for hSSB1 to function in the removal of 8-oxoguanine. Monomeric hSSB1 shows a decreased affinity for oxidized DNA resulting in a cellular 8-oxoguanine-repair defect and in the absence of ATM signaling initiation. While hSSB1 oligomerization is important for the removal of 8-oxoguanine from the genome, it is not required for the repair of double-strand DNA-breaks by homologous recombination. These findings demonstrate a novel hSSB1 regulatory mechanism for the repair of damaged DNA.

Highlights

The maintenance of genome stability is an essential cellular process to prevent the development of diseases including cancer. human single-stranded DNA binding protein 1 (hSSB1) (NABP2/ OBFC2A) is a critical component of the DNA damage response where it participates in the repair of double-strand DNA breaks and in base excision repair of oxidized guanine residues (8-oxoguanine) by aiding the localization of the human 8-oxoguanine glycosylase to damaged DNA
Given that hSSB1 relocates to damaged chromatin in response to oxidative stress[14], we sought to understand if hSSB1 function could be modulated in a similar manner
We have previously demonstrated that these concentrations are sufficient to induce oxidative stress, not to form double-strand DNA breaks

Summary

Introduction

The maintenance of genome stability is an essential cellular process to prevent the development of diseases including cancer. hSSB1 (NABP2/ OBFC2A) is a critical component of the DNA damage response where it participates in the repair of double-strand DNA breaks and in base excision repair of oxidized guanine residues (8-oxoguanine) by aiding the localization of the human 8-oxoguanine glycosylase (hOGG1) to damaged DNA. While hSSB1 oligomerization is important for the removal of 8-oxoguanine from the genome, it is not required for the repair of double-strand DNA-breaks by homologous recombination. These findings demonstrate a novel hSSB1 regulatory mechanism for the repair of damaged DNA. ROS damage DNA directly by a one electron oxidation of DNA or indirectly through the generation of reactive hydroxyl residues[2] While these reactions give rise to different products, guanine is the most commonly modified base due to its lower ionization, with 8-oxo-7,8-dihydro-guanine (8-oxoG) the most frequent modification. We have recently identified human single-stranded DNA binding protein 1 (hSSB1)/NABP2/OBFC2B as an essential component of the base excision repair pathway, functioning with hOGG1 in the repair of 8-oxoG lesions. These findings shed light on the regulation of hSSB1 function in the DNA damage response

Methods

Results

Conclusion