Translesion synthesis inhibitors as a new class of cancer chemotherapeutics

Abstract

Introduction: Translesion synthesis (TLS) is a DNA damage tolerance mechanism that replaces the replicative DNA polymerase with a specialized, low-fidelity TLS DNA polymerase that can copy past DNA lesions during active replication. Recent studies have demonstrated a primary role for TLS in replicating past DNA lesions induced by first-line genotoxic agents, resulting in decreased efficacy and acquired chemoresistance. With this in mind, targeting TLS as a combination strategy with first-line genotoxic agents has emerged as a promising approach to develop a new class of anti-cancer adjuvant agents. Areas covered: In this review, we provide a brief background on TLS and its role in cancer. We also discuss the identification and development of inhibitors that target various TLS DNA polymerases or key protein-protein interactions (PPIs) in the TLS machinery. Expert opinion: TLS inhibitors have demonstrated initial promise; however, their continued study is essential to more fully understand the clinical potential of this emerging class of anti-cancer chemotherapeutics. It will be important to determine whether a specific protein involved in TLS is an optimal target. In addition, an expanded understanding of what current genotoxic chemotherapies synergize with TLS inhibitors will guide the clinical strategies for devising combination therapies.

Keywords: DNA damage tolerance; Translesion synthesis; cancer; chemoresistance; cisplatin; lesion bypass; small-molecule inhibitors.

Figure 1.

Domains and structure of PCNA/PIP-Box PPIs. (A) Sequences of TLS polymerase PIP-box motifs. PCNA homotrimer complexed with POLκ (black, B, PDB ID 2ZVL), POLι (blue, C, PDB ID 2ZVM), POLη (red, D, PDB ID 2ZVK).

Figure 2.

Structures of REV1-CT/RIR complexes. (A) Sequences of RIR motifs in TLS DNA polymerases. Structures of REV1-CT in complex with key RIR recognition motifs from POLη (B, PDB ID 2LSK), POLκ (C, PDB ID 2LSI), and POLD3 (D, PDB ID 2N1G).

Figure 3.

Structure of the quaternary POLκ/REV1-CT/REV7/REV3 complex. (A) Full POLκ/REV1-CT/REV7/REV3 complex structure (PDB ID 4FJO). (B) and (C) Key amino acid residues at the REV7/REV3 interface.

Figure 4.

Small molecule inhibitors of TLS PPIs.

Figure 5.

Small molecule inhibitors of TLS DNA polymerases.

Figure 6.

TLS inhibitors that function through other mechanisms.