Tetraspanin protein CD53 is transiently upregulated in HSCs on stress. CD53 localizes closely to p130 and its hydratase PP2A, promoting the hypophosphorylated and active p130 form. Once dephosphorylated, p130 relocates to the nucleus and enhances DREAM complex formation, activation, and transcriptional repression of cell cycle genes, thereby promoting HSC return to quiescence. MuvB, multi-vulval class B; LIN54, Lin-54 DREAM MuvB core complex component; DP, dimerization partner. Figure created with BioRender.com.