Targeting translesion synthesis (TLS) to expose replication gaps, a unique cancer vulnerability.
Expert Opin Ther Targets
; 25(1): 27-36, 2021 01.
Article
em En
| MEDLINE
| ID: mdl-33416413
ABSTRACT
Introduction:
Translesion synthesis (TLS) is a DNA damage tolerance (DDT) mechanism that employs error-prone polymerases to bypass replication blocking DNA lesions, contributing to a gain in mutagenesis and chemo-resistance. However, recent findings illustrate an emerging role for TLS in replication gap suppression (RGS), distinct from its role in post-replication gap filling. Here, TLS protects cells from replication stress (RS)-induced toxic single-stranded DNA (ssDNA) gaps that accumulate in the wake of active replication. Intriguingly, TLS-mediated RGS is specifically observed in several cancer cell lines and contributes to their survival. Thus, targeting TLS has the potential to uniquely eradicate tumors without harming non-cancer tissues. Areas Covered This review provides an innovative perspective on the role of TLS beyond its canonical function of lesion bypass or post-replicative gap filling. We provide a comprehensive analysis that underscores the emerging role of TLS as a cancer adaptation necessary to overcome the replication stress response (RSR), an anti-cancer barrier. Expert Opinion TLS RGS is critical for tumorigenesis and is a new hallmark of cancer. Although the exact mechanism and extent of TLS dependency in cancer is still emerging, TLS inhibitors have shown promise as an anti-cancer therapy in selectively targeting this unique cancer vulnerability.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Dano ao DNA
/
Terapia de Alvo Molecular
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Neoplasias
Limite:
Animals
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Humans
Idioma:
En
Revista:
Expert Opin Ther Targets
Assunto da revista:
TERAPEUTICA
Ano de publicação:
2021
Tipo de documento:
Article