AT-rich DNA minor groove motifs at PU.1 ETS binding sites (PU.1 EBS)

The AT-rich DNA minor groove motifs at PU.1 ETS binding sites are specific genomic sequences that serve as critical docking points for the PU.1 (SPI1) transcription factor, a master regulator of myeloid and B-cell development (Antony-Debré et al., 2017, J Clin Invest). In diseases like acute myeloid leukemia (AML), PU.1 activity is often dysregulated, contributing to a block in cell differentiation and uncontrolled proliferation. These minor groove motifs are targeted by specialized small molecules, such as heterocyclic diamidines, which bind with high affinity to the AT-rich regions adjacent to the 5'-GGAA-3' core sequence. This interaction effectively displaces PU.1 from its cognate DNA sites, leading to the downregulation of oncogenic gene expression programs and the induction of terminal differentiation in leukemic blasts (Stephens et al., 2016, FEBS J). Beyond oncology, PU.1 binding sites are also investigated in neuroinflammatory contexts, such as Alzheimer's disease, where PU.1 regulates microglial activation. Targeting the DNA-protein interface at these motifs represents a precision medicine approach to modulating 'undruggable' transcription factors.

Other names

PU.1 binding siteSPI1 binding siteETS binding site minor groovePU.1-DNA interfaceAT-rich flanking sequences of PU.1 EBS

Small molecule binding to the DNA minor groove at AT-rich sequences flanking the PU.1 core binding site, resulting in competitive or allosteric inhibition of PU.1 transcription factor recruitment (Munde et al., 2014, Nucleic Acids Res).