Mutant p53 perturbs DNA replication checkpoint control through TopBP1 and Treslin
Year: 2017
Type: article
Abstract: Significance Mutant form of p53 (mutp53) proteins are expressed at high levels in many human cancers and can promote tumor cell growth. However, their mechanisms of action have not been fully understood. Elucidation of the mechanisms may identify new therapeutic strategies for treating many cancers that contain mutp53s. We describe a role for several hotspot mutp53s in reducing the checkpoint response to replication stress through interacting with TopBP1. This finding provides a rationale for a synthetic lethality strategy to treat mutp53-harboring cancer cells with inhibitors of another ATR activator, DNA2. We also find that certain mutp53s directly promote DNA replication by bridging the interaction between TopBP1 and Treslin. These results uncover mechanisms by which mutp53 enhances DNA replication.
Authors: Kang Liu, Fang-Tsyr Lin, Joshua D. Graves, Yu-Ju Lee, Weei-Chin Lin
Institution: Baylor College of Medicine
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: The ATM/E2F1 Pathway in DNA Damage and Growth Control, G1889080026, G2362353597, G2379689712, G4023538194, Novel Approaches to Target Mutant p53 Gain-of-Function in Ovarian Cancer, G6204107708, G7054895338, G7268999131, G7872248802, Targeting a Convergent Point of Multiple Oncogenic Pathways in Breast Cancer: A New Paradigm for Targeted Therapy, G863484009, Baylor College of Medicine Cancer Center - Cancer Center Support Grant, G99424851
OpenAlex ID: W2608094794