Disrupting the MAD2L2-Rev1 Complex Enhances Cell Death upon DNA Damage.

Nomi Pernicone,Tamar Listovsky,Dror Tobi,Maria Elias,Itay Onn

doi:10.3390/molecules27030636

Nomi Pernicone, Tamar Listovsky + Show 3 more

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https://doi.org/10.3390/molecules27030636

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Abstract

DNA-damaging chemotherapy agents such as cisplatin have been the first line of treatment for cancer for decades. While chemotherapy can be very effective, its long-term success is often reduced by intrinsic and acquired drug resistance, accompanied by chemotherapy-resistant secondary malignancies. Although the mechanisms causing drug resistance are quite distinct, they are directly connected to mutagenic translesion synthesis (TLS). The TLS pathway promotes DNA damage tolerance by supporting both replication opposite to a lesion and inaccurate single-strand gap filling. Interestingly, inhibiting TLS reduces both cisplatin resistance and secondary tumor formation. Therefore, TLS targeting is a promising strategy for improving chemotherapy. MAD2L2 (i.e., Rev7) is a central protein in TLS. It is an essential component of the TLS polymerase zeta (ζ), and it forms a regulatory complex with Rev1 polymerase. Here we present the discovery of two small molecules, c#2 and c#3, that directly bind both in vitro and in vivo to MAD2L2 and influence its activity. Both molecules sensitize lung cancer cell lines to cisplatin, disrupt the formation of the MAD2L2-Rev1 complex and increase DNA damage, hence underlining their potential as lead compounds for developing novel TLS inhibitors for improving chemotherapy treatments.

Highlights

DNA-damaging platinum-based chemotherapeutics have been the first line of treatment for cancer for decades
The complex was placed in a box of water, and a 30 nslong molecular dynamics simulation (MD) was conducted to determine the structural changes that occur upon binding of Rev1 to the MAD2L2 dimer
We discovered two small molecules that potentially disrupt the assembly of MAD2L2-Rev1 and the formation of an active translesion synthesis (TLS) complex

Summary

Introduction

DNA-damaging platinum-based chemotherapeutics (cisplatin, carboplatin, oxaliplatin) have been the first line of treatment for cancer for decades. They act by binding or modifying DNA and blocking replication, generating cytotoxicity and apoptosis of rapidly dividing cancer cells [1,2]. The mechanisms causing intrinsic and acquired drug resistance are quite distinct, they are directly connected to mutagenic translesion synthesis (TLS). The TLS family contains error-prone specialized polymerases. TLS is divided into a two-step mechanism, in which usually a Y-family polymerase replicates through the lesion, followed by the extension of the distorted DNA structure by Pol ζ. The Pol ζ core complex contains two proteins, the polymerase catalytic subunit Rev and a regulatory subunit MAD2L2

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