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Induction of programmed DNA damage and its recognition and repair are fundamental for B cell development. The ssDNA-binding protein SSB1 has been described in human cells as essential for the recognition and repair of DNA damage. To study its relevance for B cells, we recently developed Ssb1  -/- and conditional Ssb1  -/- mice. Although SSB1 loss did not affect B cell development, Ssb1  -/- cells exhibited compensatory expression of its homolog SSB2. We have now generated Ssb2  -/- mice and show in this study that SSB2 is also dispensable for B cell development and DNA damage response activation. In contrast to the single loss of Ssb1 or Ssb2 , however, combined SSB1/2 deficiency caused a defect in early B cell development. We relate this to the sensitivity of B cell precursors as mature B cells largely tolerated their loss. Toxicity of combined genetic SSB1/2 loss can be rescued by ectopic expression of either SSB1 or SSB2, mimicked by expression of SSB1 ssDNA-binding mutants, and attenuated by BCL2-mediated suppression of apoptosis. SSB1/2 loss in B cell precursors further caused increased exposure of ssDNA associated with disruption of genome fragile sites, inefficient cell cycle progression, and increased DNA damage if apoptosis is suppressed. As such, our results establish SSB1/2 as safeguards of B cell development and unveil their differential requirement in immature and mature B lymphocytes.

SSB1/SSB2 Proteins Safeguard B Cell Development by Protecting the Genomes of B Cell Precursors