Deregulated protein homeostasis constrains fetal hematopoietic stem cell pool expansion in Fanconi anemia.

ABSTRACT: Demand-adjusted and cell type specific rates of protein synthesis represent an important safeguard for fate and function of long-term hematopoietic stem cells. Here, we identify increased protein synthesis rates in the fetal hematopoietic stem cell pool at the onset of hematopoietic failure in Fanconi Anemia, a prototypical DNA repair disorder that manifests with bone marrow failure. Mechanistically, the accumulation of misfolded proteins in Fancd2^-/- fetal liver hematopoietic stem cells converges on endoplasmic reticulum stress, which in turn constrains midgestational expansion. Restoration of protein folding by the chemical chaperone tauroursodeoxycholic acid, a hydrophilic bile salt, prevents accumulation of unfolded proteins and rescues Fancd2^-/- fetal liver long-

SUBMITTER: Kovuru N 

PROVIDER: S-EPMC10904799 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature