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

Sumeet Nayak1, Jennifer A Calvo1, Sharon B Cantor1

  • 1Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School , Worcester, MA USA.

Expert Opinion on Therapeutic Targets
|January 8, 2021
PubMed

Insights

Translesion synthesis (TLS) is crucial for cancer survival by suppressing toxic DNA gaps during replication stress. Targeting TLS offers a promising strategy for cancer therapy, selectively eliminating tumor cells.

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.
Keywords:
DNA lesion bypassTranslesion synthesis (TLS)cancer and cancer therapeuticsmutagenesisoncogene-induced replication stressreplication gap suppression (RGS)replication stress response (RSR)ssDNA gaps

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