Abstract
The gene encoding DNA polymerase θ (Polθ) was discovered over ten years ago as having a role in suppressing genome instability in mammalian cells. Studies have now clearly documented an essential function for this unique A-family polymerase in the double-strand break (DSB) repair pathway alternative end-joining (alt-EJ), also known as microhomology-mediated end-joining (MMEJ), in metazoans. Biochemical and cellular studies show that Polθ exhibits a unique ability to perform alt-EJ and during this process the polymerase generates insertion mutations due to its robust terminal transferase activity which involves template-dependent and independent modes of DNA synthesis. Intriguingly, the POLQ gene also encodes for a conserved superfamily 2 Hel308-type ATP-dependent helicase domain which likely assists in alt-EJ and was reported to suppress homologous recombination (HR) via its anti-recombinase activity. Here, we review our current knowledge of Polθ-mediated end-joining, the specific activities of the polymerase and helicase domains, and put into perspective how this multifunctional enzyme promotes alt-EJ repair of DSBs formed during S and G2 cell cycle phases.
Highlights
The chaos1 mutation in mice was discovered over 10 years ago as promoting a cellular phenotype, characterized by a high frequency of spontaneous and radiation, induced micronuclei in circulating red blood cells which are caused by defects in DNA repair or cell division [1]
Given that this particular mutation results in a major amino acid change from serine to proline in the Polq1 gene, this seminal discovery stimulated a new line of research aimed at elucidating the function of this previously uncharacterized gene product referred to as polymerase θ (Polθ) which includes a C-terminal A-family DNA polymerase and an N-terminal superfamily
It has been well documented that Polθ repairs double-strand break (DSB) via the alternative end-joining (alt-EJ) pathway, and mounting evidence suggests that this process is exclusively activated during S-phase and likely involved in replication repair
Summary
The chaos (chromosome aberration occurring spontaneously 1) mutation in mice was discovered over 10 years ago as promoting a cellular phenotype, characterized by a high frequency of spontaneous and radiation, induced micronuclei in circulating red blood cells which are caused by defects in DNA repair or cell division [1] Given that this particular mutation results in a major amino acid change from serine to proline in the Polq gene, this seminal discovery stimulated a new line of research aimed at elucidating the function of this previously uncharacterized gene product referred to as Polθ which includes a C-terminal A-family DNA polymerase and an N-terminal superfamily.
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