Biology subjects

Sahay, H.

Publications and source records attributed to Sahay, H..

2 recordsLinked to original sources

bioRxiv2026

A pan-cancer catalog of mutagenesis at transcription factor binding sites

Transcription factor (TF) binding can contribute to mutagenesis by altering DNA damage formation or interfering with DNA repair. Although these effects have been characterized for selected TFs and mutagenic processes, their prevalence across TFs and cancer types remains poorly understood. A systematic characterization of mutation enrichment at TF binding sites is needed to guide mechanistic studies and improve the interpretation of noncoding mutations in cancer. Here, we analyzed somatic mutations from over 4,000 tumors across 15 tissue types to generate a pan-cancer catalog of mutation patterns at binding sites for 655 TFs, organized into 276 motif clusters. We assessed mutation enrichment at single-nucleotide resolution, accounting for sequence-dependent and local variation in background mutation rates. Nearly one third of pairs with sufficient mutation counts showed significant enrichment at one or more binding site positions. Enrichment was most widespread in melanoma but was detected in all 15 tissue types, with the affected TFs and binding site positions varying across tissues. Highly expressed TFs were more likely to show enrichment than lowly expressed TFs, consistent with a role for TF binding in increased mutagenesis at the binding sites. Mutational signature analysis implicated processes beyond UV damage, including age-associated processes, deamination lesions, oxidative damage, and tobacco exposure, as potentially contributing to TF-induced mutagenesis. Together, these findings suggest that diverse interactions between TF binding, DNA damage, and DNA repair may contribute to mutation enrichment in regulatory DNA. Our pan-cancer catalog reveals position-specific enrichment of somatic mutations at TF binding sites across all 15 tissue types analyzed. By identifying specific TFs and binding site positions enriched for somatic mutations, together with potential mutagenic processes acting at these positions, our study provides a roadmap for experimental assessment of TF-induced mutagenesis and informs the interpretation and prioritization of non-coding mutations in cancer.

cancer biology↗

bioRxiv2019

DNA mismatches reveal widespread conformational penalties in protein-DNA recognition

Transcription-factor (TF) proteins recognize specific genomic sequences, despite an overwhelming excess of non-specific DNA, to regulate complex gene expression programs1-3. While there have been significant advances in understanding how DNA sequence and shape contribute to recognition, some fundamental aspects of protein-DNA binding remain poorly understood2,3. Many DNA-binding proteins induce changes in the DNA structure outside the intrinsic B-DNA envelope. How the energetic cost associated with distorting DNA contributes to recognition has proven difficult to study and measure experimentally because the distorted DNA structures exist as low-abundance conformations in the naked B-DNA ensemble4-10. Here, we use a novel high-throughput assay called SaMBA (Saturation Mismatch-Binding Assay) to investigate the role of DNA conformational penalties in TF-DNA recognition. The approach introduces mismatched base-pairs (i.e. mispairs) within TF binding sites to pre-induce a variety of DNA structural distortions much larger than those induced by changes in Watson-Crick sequence. Strikingly, while most mismatches either weakened TF binding (~70%) or had negligible effects (~20%), approximately 10% of mismatches increased binding and at least one mismatch was found that increased the binding affinity for each of 21 examined TFs. Mismatches also converted sites from the non-specific affinity range into specific sites, and high-affinity sites into \"super-sites\" stronger than any known canonical binding site. These findings reveal a complex binding landscape that cannot be explained based on DNA sequence alone. Analysis of crystal structures together with NMR and molecular dynamics simulations revealed that many of the mismatches that increase binding induce distortions similar to those induced by TF binding, thus pre-paying some of the energetic cost to deform the DNA. Our work indicates that conformational penalties are a major determinant of protein-DNA recognition, and reveals mechanisms by which mismatches can recruit TFs and thus modulate replication and repair activities in the cell11,12.

biophysics↗