PICH Supports Embryonic Hematopoiesis by Suppressing a cGAS-STING-Mediated Interferon Response.
Xinwei GengChao ZhangMiao LiJiaqi WangFang JiHanrong FengMeichun XingFei LiLingling ZhangWen LiZhihua ChenIan D HicksonHuahao ShenSongmin YingPublished in: Advanced science (Weinheim, Baden-Wurttemberg, Germany) (2022)
The Plk1-interacting checkpoint helicase (PICH) protein localizes to ultrafine anaphase DNA bridges in mitosis along with a complex of DNA repair proteins. Previous studies show PICH deficiency-induced embryonic lethality in mice. However, the function of PICH that is required to suppress embryonic lethality in PICH-deficient mammals remains to be determined. Previous clinical studies suggest a link between PICH deficiency and the onset of acquired aplastic anemia. Here, using Pich knock-out (KO) mouse models, the authors provide evidence for a mechanistic link between PICH deficiency and defective hematopoiesis. Fetal livers from Pich-KO embryos exhibit a significantly elevated number of hematopoietic stem cells (HSCs); however, these HSCs display a higher level of apoptosis and a much-reduced ability to reconstitute a functional hematopoietic system when transplanted into lethally irradiated recipients. Moreover, these HSCs show an elevated cytoplasmic dsDNA expression and an activation of the cGAS-STING pathway, resulting in excessive production of type I interferons (IFN). Importantly, deletion of Ifnar1 or cGAS reverses the defective hematopoiesis. The authors conclude that loss of PICH results in defective hematopoiesis via cGAS-STING-mediated type I IFN production.
Keyphrases
- dna repair
- stem cells
- dna damage
- immune response
- type diabetes
- poor prognosis
- replacement therapy
- binding protein
- single molecule
- cell proliferation
- endoplasmic reticulum stress
- signaling pathway
- small molecule
- physical activity
- acute lymphoblastic leukemia
- air pollution
- endothelial cells
- long non coding rna
- dna damage response
- particulate matter
- pi k akt