Ssb1 and Ssb2 protect genome integrity, via promoting resolution of R-loops during transcription, and facilitate telomere maintenance (A). Shi et al demonstrate that compound loss of Ssb1 and Ssb2 in HSCs leads to replication stress and DNA breaks at actively transcribed sites prone to R-loop formation. This leads to accumulation of intracellular ssDNA, production of IFNs, and loss of quiescence, which drives HSC depletion and BMF at least in part via a p53-dependent mechanism (B). Collectively, these findings provide insight into the mechanisms by which faulty DNA repair can induce BMF. See the complete Figure 7 in the article by Shi et al that begins on page 2479. DDR, DNA damage response; WT, wild-type.