Mounting evidence has shown that histone acetyltransferase binding to ORC1 (HBO1) serves as an oncoprotein, warranting the use of the small molecule inhibitor WM-3835 for cancer therapy. However, HBO1 is ubiquitously expressed in both tumor and normal tissues, with potential to increase the risk of systemic toxicity. This unmet need highlights the importance of identifying suitable biomarkers to predict the sensitivity to HBO1 inhibitor. Here, we show that ATR, a key regulator of DNA replication stress, is a novel interacting partner of HBO1. Additionally, we reveal a regulatory function of HBO1 in DNA replication stress responses, in an ATR-dependent manner. Mechanistically, ATR mediated HBO1 Ser50/53 phosphorylation interferes with the genomic binding of HBO1 and regulates gene expression. Notably, overexpression of HBO1 mutated at the ATR phosphorylation site (S50/53A) dampens the expression of DNA repair related genes and suppresses tumor colony formation, consistent with the observations of WM-3835 treatment. Inhibition of ATR significantly antagonized the sensitivity to WM-3835 treatment. Collectively, our findings uncovered a previously unidentified role of HBO1 in the regulation of replication stress and discovered ATR as a potential biomarker for WM-3835 treatment.
C. Zong, Jiamin Zhang, Zhe Zhang et al.· Journal of Biological Chemis...· 0 citations
Acute myeloid leukemia (AML) represents a type of malignant hematological disease that is usually caused by the dysregulated developmental program of leukemia stem cells (LSCs). Here, we report that an unappreciated RNA-binding protein, Rbm5, selectively promotes murine leukemogenesis, maintains LSC self-renewal in vivo, and is dispensable for normal hematopoiesis. Rbm5 is highly expressed in LSCs, and its deficiency results in specifically defective LSC function, along with inhibition of self-renewal gene expression and induction of myeloid differentiation. Multi-disciplinary mechanistic investigations further identified Myc as the major and direct transcriptional target of Rbm5 in primary leukemia cells. Moreover, RBM5 not only interacts with MYC but also maintains its protein levels, thereby sustaining the Myc downstream transcriptional network through its proper genome-wide occupancy. Forced expression of Myc sufficiently rescued the Rbm5-depleted LSC defects. Thus, our study demonstrates that Rbm5 regulates the AML LSC program through non-canonical transcriptional mechanisms, providing a strong rationale for targeting Rbm5 therapeutically. In Brief. Zhang et al. illustrate the role of Rbm5 in sustaining the self-renewal program in leukemia stem. cells (LSCs) primarily through the Myc transcriptional network. Specifically, Rbm5 loss results in a significant decrease in Myc protein levels, thereby disrupting. the Myc downstream transcriptional network in LSCs. Notably, this effect is specific to LSCs, as. normal hematopoietic stem cells (HSCs) do not exhibit such changes upon Rbm5 loss.
