DCAF13 Safeguards Hematopoietic Stem Cells via RRS1‐Regulated Ribosome Biogenesis

ABSTRACT Hematopoietic stem cells (HSCs) sustain lifelong blood production by balancing self‐renewal and differentiation. The mechanisms regulating HSC homeostasis, particularly those involving ribosome biogenesis, remain incompletely understood. Here, we identify DCAF13 as a critical regulator of HSC maintenance by stabilizing RRS1, a key factor in ribosome biogenesis. Conditional deletion of Dcaf13 in murine hematopoietic cells results in severe pancytopenia, rapid mortality, and complete HSC depletion in both fetal and adult hematopoietic compartments. We show that DCAF13 deficiency disrupts ribosome assembly and protein synthesis, selectively affecting the translation of mRNAs from genes involved in myeloid differentiation, chromatin remodeling, and erythroid homeostasis. DCAF13 directly binds RRS1 and catalyzes its K27‐linked polyubiquitination, a non‐degradative post‐translational modification that enhances RRS1 protein stability.While Dcaf13 deletion activates the p53 pathway, Trp53 ablation only partially restores HSC numbers and cell cycle progression, and does not prevent apoptosis and hematopoietic failure, indicating the involvement of both p53‐dependent and p53‐independent mechanisms. These findings establish a DCAF13‐RRS1 axis essential for HSC function, in which DCAF13 acts as an essential regulator of ribosome biogenesis. This work provides molecular insights into the pathogenesis of hematopoietic disorders and ribosomopathies.