Targeting translesion synthesis (TLS) to expose replication gaps, a unique cancer vulnerability.

Area of Science:

• Molecular Biology
• Cancer Biology
• Genetics

Background:

• Translesion synthesis (TLS) is a DNA damage tolerance mechanism.
• TLS typically bypasses DNA lesions using error-prone polymerases, aiding mutagenesis and chemo-resistance.
• Emerging evidence highlights TLS's role in replication gap suppression (RGS), distinct from post-replication gap filling.

Purpose of the Study:

• To provide an innovative perspective on TLS beyond its canonical functions.
• To analyze the emerging role of TLS in cancer adaptation and overcoming replication stress.
• To underscore the significance of TLS-mediated RGS in cancer cell survival.

Main Methods:

• Literature review and comprehensive analysis of existing research on TLS.
• Focus on studies investigating TLS in the context of replication stress and cancer.
• Examination of TLS's role in replication gap suppression (RGS).

Main Results:

• TLS protects cells from toxic single-stranded DNA (ssDNA) gaps that arise during replication stress.
• TLS-mediated RGS is observed in several cancer cell lines, contributing to their survival.
• TLS acts as a cancer adaptation to overcome the replication stress response (RSR).

Conclusions:

• TLS-mediated RGS is critical for tumorigenesis and represents a new hallmark of cancer.
• Targeting TLS has the potential to selectively eradicate tumors.
• TLS inhibitors show promise as an anti-cancer therapy by exploiting cancer-specific vulnerabilities.