Mutant p53 perturbs DNA replication checkpoint control through TopBP1 and Treslin

Area of Science:

• Molecular Biology
• Cancer Research
• Cell Cycle Regulation

Background:

• Mutant forms of p53 (mutp53s) exhibit gain-of-function properties.
• Topoisomerase Binding Protein 1 (TopBP1) is crucial for activating the ATR checkpoint response.
• Akt-mediated phosphorylation of TopBP1 inhibits its ATR-activating function.

Purpose of the Study:

• To investigate whether mutp53 directly perturbs the DNA replication checkpoint.
• To elucidate the mechanisms by which mutp53 interferes with TopBP1 function.
• To explore therapeutic strategies exploiting mutp53's effect on DNA replication.

Main Methods:

• Cellular assays to assess TopBP1 oligomerization and ATR checkpoint response.
• Analysis of TopBP1 interactions with Treslin and p53 mutants.
• Synthetic lethality experiments involving DNA2 depletion or inhibition in cancer cells expressing mutp53.

Main Results:

• Various mutp53s, both contact and conformational, bypass Akt to induce TopBP1 oligomerization, attenuating the ATR checkpoint response during replication stress.
• Depletion of DNA2 in mutp53-R273H-expressing cancer cells resulted in hypersensitivity to cisplatin.
• Contact mutp53s, but not conformational ones, enhance the TopBP1/Treslin interaction, promoting DNA replication independently of Cdk2 inhibition.

Conclusions:

• Mutp53 attenuates the ATR checkpoint response to replication stress via TopBP1, offering a synthetic lethality vulnerability.
• Mutp53 promotes DNA replication during normal growth by facilitating the TopBP1/Treslin interaction, overriding Cdk2 dependence.
• Targeting DNA2 in conjunction with mutp53 expression presents a promising therapeutic strategy for cancer treatment.