Nucleotide depletion promotes cell fate transitions by inducing DNA replication stress.

ABSTRACT: Control of cellular identity requires coordination of developmental programs with environmental factors such as nutrient availability, suggesting that perturbing metabolism can alter cell state. Here, we find that nucleotide depletion and DNA replication stress drive differentiation in human and murine normal and transformed hematopoietic systems, including patient-derived acute myeloid leukemia (AML) xenografts. These cell state transitions begin during S phase and are independent of ATR/ATM checkpoint signaling, double-stranded DNA break formation, and changes in cell cycle length. In systems where differentiation is blocked by oncogenic transcription factor expression, replication stress activates primed regulatory loci and induces lineage-appropriate maturation genes despite the persis

SUBMITTER: Do BT 

PROVIDER: S-EPMC11444020 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature