Samano-Sanchez, H. | Search bioRxiv

bioRxiv2026

A Non-Canonical Role of SMAD4 in Regulating 3D Genome Architecture to Inhibit Lung Squamous Cell Carcinoma Development

Lung squamous cell carcinoma (LUSC) lacks clearly defined key drivers and effective targeted therapies, reflecting an incomplete understanding of its molecular pathogenesis. Here, we identify SMAD4 as a critical regulator of three-dimensional (3D) genome organization in LUSC and uncover a mechanistic link between tumor suppressor loss and oncogenic transcriptional activation. By integrating clinical datasets, genetically engineered mouse models, human and murine LUSC cell lines, and multi-omics analyses, we demonstrate that SMAD4 deficiency promotes LUSC progression by unleashing EP300-mediated enhancer-promoter looping at the SOX2 locus. Mechanistically, SMAD4 does not directly bind SOX2 regulatory elements but instead constrains chromatin looping by sequestering EP300 away from loop anchor regions. Loss of SMAD4 leads to enhanced H3K27ac deposition, aberrant SOX2 activation, and increased LUSC tumor cell proliferation. Together, these findings reveal a non-canonical role for a transcription factor (e.g., SMAD4) in regulating dysregulated 3D genome architecture to inhibit tumor development.

cancer biology↗

bioRxiv2018

Conserved SQ and QS motifs in bacterial effectors suggest pathogen interplay with the ATM kinase family during infection

Understanding how bacteria hijack eukaryotic cells during infection is vital to develop better strategies to counter the pathologies that they cause. ATM kinase family members phosphorylate eukaryotic protein substrates on Ser or Thr residues followed by Gln. The kinases are active under oxidative stress conditions and/or the presence of ds-DNA breaks. While examining the protein sequences of well-known bacterial effector proteins such as CagA and Tir, we noticed that they often show conserved (S/TQ) motifs, even though the evidence for effector phosphorylation by ATM has not been reported. We undertook a bioinformatics analysis to examine effectors for their potential to mimic the eukaryotic substrates of the ATM kinase. The candidates we found could interfere with the hosts intracellular signaling network upon interaction, which might give an advantage to the pathogen inside the host. Further, the putative phosphorylation sites should be accessible, conserved across species and, in the vicinity to the phosphorylation sites, positively charged residues should be depleted. We also noticed that the reverse motif (QT/S) is often also conserved and located close to (S/TQ) sites, indicating its potential biological role in ATM kinase function. Our findings could suggest a mechanism of infection whereby many pathogens inactivate/modulate the host ATM signaling pathway.

bioinformatics↗