SRA

Hematopoietic stress drives quiescent hematopoietic stem cells (HSCs) to proliferate, generating reactive oxygen species and oxidative DNA damage including abasic sites. The coupling between abasic site generation and DNA replication during HSC stress responses, however, presents a challenge to accurately repair these abasic sites in the single-stranded DNA (ssDNA) generated during replication, leading to strand breaks and mutations. Here, we show in mice that HMCES, an evolutionarily conserved sensor and shield of ssDNA abasic sites, plays a pivotal role in overcoming this challenge. Hmces-deficient HSCs exhibited compromised long-term self-renewal capacity and elevated DNA damage in vivo in response to various hematopoietic stress, as well as broad attenuation of DNA damage response and repair pathways. Loss of HMCES also rendered HSCs hypersensitive to alcohol-derived acetaldehyde and might associate with increased susceptibility of leukemia. Collectively, our findings highlighted HMCES as a novel protector of HSCs and shed light on its physiological roles in regeneration and tumorigenesis. Overall design: LT-HSCs of WT and Hmces knockout for duplicates are performed RNA sequencing.