Cancer-associated TRF1 mutations alter PARP1 interaction dynamics: an in silico study.

Abstract

Telomeric repeat-binding factor 1 (TRF1), a core component of the shelterin complex, is essential for preserving telomere integrity by facilitating efficient replication fork progression across G-rich telomeric DNA. Through its interaction with poly (ADP-ribose) polymerase 1 (PARP1), TRF1 contributes to telomeric chromatin organization and supports the recruitment of helicases required to resolve replication-associated barriers. PARP1 is a central regulator of DNA repair and fork protection, navigating chromatin through a dynamic “monkey-bar” transfer mechanism in which its domains alternately engage distinct DNA sites. Pharmacological inhibition disrupts this dynamic behavior and induces PARP trapping, a cytotoxic state exploited therapeutically in DNA repair-deficient cancers. To explore whether TRF1 mutations could modulate PARP1 interaction dynamics in a manner conceptually analogous to trapping, we employed an integrative in silico pipeline combining pathogenicity prediction, structural modeling, protein-protein docking, and molecular dynamics simulations. Among mutations reported in COSMIC and dbSNP, four variants (D422G, W424L, R425G, and M427K) emerged as candidates with high disruptive potential, with the Myb-domain variant W424L prioritized for detailed analysis. Structural and dynamic analyses revealed that the W424L substitution alters local TRF1–PARP1 contact networks and biases PARP1 toward a more conformationally constrained interaction state, without altering the primary interface geometry. Collectively, these findings support a model in which specific TRF1 mutations may reprogram PARP1 interaction dynamics at telomeres. While experimental validation will be required, this work provides a hypothesis-generating framework suggesting that TRF1 variant profiling may help identify tumors with altered PARP1 dependency and differential sensitivity to PARP-targeted therapies.