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Sengupta P, Gillet N, Obi I, Sabouri N
Nat Commun 17 (1) 1149 [2026-02-02; online 2026-02-02]
I-motifs are non-canonical, four-stranded DNA structures in cytosine-rich genomic regions, yet their protein-mediated regulation remains underexplored. Here, we identify PCBP1 (Poly(rC)-binding protein 1) as a selective i-motif-binding protein that unfolds specific i-motifs depending on their protonation and hairpin-forming propensities. Systematic truncation reveals that individual K-homology (KH) domains of PCBP1 cannot selectively bind or unfold i-motifs, but their coordinated actions restore wild-type PCBP1 functions. Using biochemical, biophysical, and molecular dynamics studies, we demonstrate that KH1+2 domains remodel i-motifs, recruiting KH3 to facilitate unfolding and efficient DNA replication. Chromatin and cell-based investigations reveal that PCBP1-knockdown increases i-motif formation at specific genomic loci, coinciding with G1/S arrest and elevated γH2AX, indicative of genomic instability. During G1/S transition, PCBP1 occupancy peaks at these i-motif loci, ensuring i-motif resolution in early S phase. These findings establish PCBP1 as a critical regulator of i-motif dynamics, directly linking its unfolding activity to G1/S transition and genome stability.
PubMed 41629296
DOI 10.1038/s41467-026-68822-5
Crossref 10.1038/s41467-026-68822-5
pii: 10.1038/s41467-026-68822-5
pmc: PMC12865031