hSSB1 (NABP2/ OBFC2B) is required for the repair of 8-oxo-guanine by the hOGG1-mediated base excision repair pathway

Abstract

The maintenance of genome stability is essential to prevent loss of genetic information and the development of diseases such as cancer. One of the most common forms of damage to the genetic code is the oxidation of DNA by reactive oxygen species (ROS), of which 8-oxo-7,8-dihydro-guanine (8-oxoG) is the most frequent modification. Previous studies have established that human single-stranded DNA-binding protein 1 (hSSB1) is essential for the repair of double-stranded DNA breaks by the process of homologous recombination. Here we show that hSSB1 is also required following oxidative damage. Cells lacking hSSB1 are sensitive to oxidizing agents, have deficient ATM and p53 activation and cannot effectively repair 8-oxoGs. Furthermore, we demonstrate that hSSB1 forms a complex with the human oxo-guanine glycosylase 1 (hOGG1) and is important for hOGG1 localization to the damaged chromatin. In vitro, hSSB1 binds directly to DNA containing 8-oxoguanines and enhances hOGG1 activity. These results underpin the crucial role hSSB1 plays as a guardian of the genome.

hSSB1 (NABP2/OBFC2B) is regulated by oxidative stress

“…While our previous results demonstrate that hSSB1 and hOGG1 form a complex within cells14. The inability of the C41S hSSB1 mutant to rescue the hSSB1-depleted cells may therefore be due to disruption of this complex.…”

Ssb1 and Ssb2 cooperate to regulate mouse hematopoietic stem and progenitor cells by resolving replicative stress

“…[3][4][5][6][7][8] Our generation and phenotypic analysis of cDKO mice has unmasked the compensatory and essential functions of Ssb1/Ssb2 in maintaining tissue homeostasis, which was unexpected from analysis of single knockout mouse models.…”

“…Depletion of SSB1 in cells results in increased radiosensitivity, defective repair of DNA double-strand breaks (DSBs), oxidative DNA damage, and failure to restart stalled replication forks. [3][4][5][6][7][8] Moreover, Ssb1 has been shown to regulate telomere homeostasis by protecting newly replicated G-overhangs of leading-and lagging-strand telomeres. 9,10 SSB1 is recurrently mutated in various cancers, and an SSB2/RARA fusion gene has been described in variant acute promyelocytic leukemia.…”

Novel insight into the composition of human single-stranded DNA-binding protein 1 (hSSB1)-containing protein complexes

“…Here, hSSB1 has been reported to stimulate resection of double-strand DNA break ends by the Mre11-Nbs1-Rad50 (MRN) [22, 23] and Exo1 [24] nucleases, as well as activation of the ATM kinase [20]. Additional roles for hSSB1 have also been reported in the response to replication fork stalling [21, 25], as well as in oxidative stress repair [26, 27]. …”