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Mechanism, cellular functions and cancer roles of polymerase-theta-mediated DNA end joining

Dale A Ramsden1,2,3, Juan Carvajal-Garcia4, Gaorav P Gupta5,6,7,8

  • 1Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. dale_ramsden@med.unc.edu.

Nature Reviews. Molecular Cell Biology
|September 15, 2021
PubMed

Insights

Alternative end joining (a-EJ), mediated by DNA polymerase theta (Polθ), repairs challenging DNA double-strand breaks (DSBs). This pathway, termed Polθ-mediated end joining (TMEJ), has implications for genome stability and cancer therapy.

Area of Science:

  • Molecular Biology
  • Genetics
  • Cancer Research

Background:

  • Cellular pathways repairing DNA double-strand breaks (DSBs) are crucial for cell growth, development, and cancer.
  • Alternative end joining (a-EJ), a DSB repair pathway, has remained poorly understood.
  • Non-homologous end joining (NHEJ) is a primary DSB repair mechanism, but alternative pathways exist.

Purpose of the Study:

  • To review recent advancements in understanding the alternative end joining (a-EJ) pathway.
  • To highlight the role of DNA polymerase theta (Polθ) as the primary mediator of a-EJ.
  • To discuss the molecular mechanisms and cellular functions of Polθ-mediated end joining (TMEJ).

Main Methods:

  • Literature review of recent studies on a-EJ and Polθ.
  • Analysis of proposed molecular mechanisms for TMEJ.
  • Discussion of cellular contexts where TMEJ operates.

Main Results:

  • DNA polymerase theta (Polθ) is identified as the predominant mediator of a-EJ in most eukaryotes.
  • A potential molecular mechanism for Polθ-mediated end joining (TMEJ) is proposed.
  • TMEJ resolves various types of DSBs, including those resistant to NHEJ, those from replication fork collapse, and those from stalled homologous recombination.

Conclusions:

  • TMEJ plays context-dependent roles in resolving difficult DSBs.
  • TMEJ can contribute to both genome stability and instability.
  • Polθ represents a potential therapeutic target for cancer treatment.

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