Hematopoietic stress drives quiescent hematopoietic stem cells (HSCs) to proliferate, generating reactive oxygen species (ROS) and oxidative DNA damage including abasic sites. Such a coupling between rapid DNA replication and a burst of abasic site formation during HSC stress responses, however, presents a challenge to accurately repair abasic sites located in replication-associated single-stranded DNA. Here we show that HMCES, a novel shield of abasic sites, plays pivotal roles in overcoming this challenge upon HSC activation. While HMCES was dispensable for steady-state hematopoiesis, Hmces-deficient HSCs exhibited compromised long-term self-renewal capacity in response to hematopoietic stress such as myeloablation and transplantation. Loss of HMCES resulted in accumulation of DNA lesions due to impaired resolution of abasic sites generated by activation-induced ROS in activated HSCs and broad downregulation of DNA damage response and repair pathways. Moreover, Hmces-deficient mice died from bone marrow failure after exposure to sublethal irradiation, which also produces ROS. Notably, dysregulation of HMCES occurs frequently in acute lymphocytic leukemia (ALL) and is associated with poor clinical outcomes. Together, our findings not only highlighted HMCES as a novel genome protector in activated HSCs, but also position it as a potential selective target against ALL while sparing normal hematopoiesis.
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RNA-seq data generated in this study have been deposited in the Gene Expression Omnibus database under accession number GSE150721.
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We thank Drs. Lei Li, Pinglong Xu, and Pengxu Qian for helpful comments and discussions. We are also grateful to Meilei Sheng, Shu Qiang and the core facility of Life Sciences Institute at Zhejiang University for technical assistance. This project was supported by National Natural Science Foundation of China (32022023, 31871478, 81770155, 82022026), National Key Research and Development Programs of China (2017YFC1001500, 2018YFA0109300, 2017YFA0103302), Zhejiang Provincial Natural Science Foundation of China (LR18C060001), Science Foundation for Distinguished Young Scholars of Guangdong Province (2019B151502008), and Fundamental Research Funds for the Central Universities.
The authors declare no competing interests.
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Pan, Y., Zuo, H., Wen, F. et al. HMCES safeguards genome integrity and long-term self-renewal of hematopoietic stem cells during stress responses. Leukemia 36, 1123–1131 (2022). https://doi.org/10.1038/s41375-021-01499-5