Essential Developmental, Genomic Stability, and Tumour Suppressor Functions of the Mouse Orthologue of hSSB1/NABP2

Abstract

Single-stranded DNA binding proteins (SSBs) regulate multiple DNA transactions, including replication, transcription, and repair. We recently identified SSB1 as a novel protein critical for the initiation of ATM signaling and DNA double-strand break repair by homologous recombination. Here we report that germline Ssb1 ^−/− embryos die at birth from respiratory failure due to severe rib cage malformation and impaired alveolar development, coupled with additional skeletal defects. Unexpectedly, Ssb1 ^−/− fibroblasts did not exhibit defects in Atm signaling or γ-H2ax focus kinetics in response to ionizing radiation (IR), and B-cell specific deletion of Ssb1 did not affect class-switch recombination in vitro. However, conditional deletion of Ssb1 in adult mice led to increased cancer susceptibility with broad tumour spectrum, impaired male fertility with testicular degeneration, and increased radiosensitivity and IR–induced chromosome breaks in vivo. Collectively, these results demonstrate essential roles of Ssb1 in embryogenesis, spermatogenesis, and genome stability in vivo.

Author Summary

Single-stranded DNA binding proteins (SSBs) play a variety of roles in the cell, regulating transcription, replication, and DNA repair. We recently identified and described a novel SSB, designated SSB1, which was shown to be critical for DNA repair in the cell. In this study we have used a mouse model in which the Ssb1 gene is deleted to further investigate its physiological function. Here, we show that deletion of Ssb1 causes death at birth due to severe respiratory failure, which is caused by an improperly formed rib cage and immature lung development. In addition, we observed multiple additional skeletal defects in Ssb1 deleted mice, indicating that Ssb1 is necessary for proper development of the embryonic skeleton. Furthermore, Ssb1 deletion in the adult mouse caused fertility defects in male mice and led to the development of a variety of tumours. Together, these studies demonstrate a novel and critical role of Ssb1 in embryonic development, in fertility, and in the protection from tumour formation.