TopBP1 biomolecular condensates as a new therapeutic target in advanced-stage colorectal cancer.

ABSTRACT: In cancer cells, ATR signaling is crucial to tolerate the intrinsically high damage levels that normally block replication fork progression. Assembly of TopBP1, a multifunctional scaffolding protein, into condensates is required to amplify ATR kinase activity to the levels needed to coordinate the DNA damage response and manage DNA replication stress. Many ATR inhibitors are tested for cancer treatment in clinical trials, but their overall effectiveness is often compromised by the emergence of resistance and toxicities. In this proof-of-concept study, we propose to disrupt the ATR pathway by targeting TopBP1 condensation. First, we screened a molecule-based library using a previously developed optogenetic approach and identified several TopBP1 condensation inhibitors. Among them, AZD2858 d

SUBMITTER: Morano L 

PROVIDER: S-EPMC12539802 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature