Genetic determinants of cellular addiction to DNA polymerase theta

Wanjuan Feng, Dennis A. Simpson, Juan Carvajal-Garcia, Brandon A. Price, Rashmi J. Kumar, Lisle E. Mose, Richard D. Wood, Naim Rashid, Jeremy E. Purvis, Joel S. Parker, Dale A. Ramsden and Gaorav P. Gupta ()
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Wanjuan Feng: University of North Carolina at Chapel Hill
Dennis A. Simpson: University of North Carolina at Chapel Hill
Juan Carvajal-Garcia: University of North Carolina at Chapel Hill
Brandon A. Price: University of North Carolina at Chapel Hill
Rashmi J. Kumar: University of North Carolina at Chapel Hill
Lisle E. Mose: University of North Carolina at Chapel Hill
Richard D. Wood: University of Texas MD Anderson Cancer Center
Naim Rashid: University of North Carolina at Chapel Hill
Jeremy E. Purvis: University of North Carolina at Chapel Hill
Joel S. Parker: University of North Carolina at Chapel Hill
Dale A. Ramsden: University of North Carolina at Chapel Hill
Gaorav P. Gupta: University of North Carolina at Chapel Hill

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: Abstract Polymerase theta (Pol θ, gene name Polq) is a widely conserved DNA polymerase that mediates a microhomology-mediated, error-prone, double strand break (DSB) repair pathway, referred to as Theta Mediated End Joining (TMEJ). Cells with homologous recombination deficiency are reliant on TMEJ for DSB repair. It is unknown whether deficiencies in other components of the DNA damage response (DDR) also result in Pol θ addiction. Here we use a CRISPR genetic screen to uncover 140 Polq synthetic lethal (PolqSL) genes, the majority of which were previously unknown. Functional analyses indicate that Pol θ/TMEJ addiction is associated with increased levels of replication-associated DSBs, regardless of the initial source of damage. We further demonstrate that approximately 30% of TCGA breast cancers have genetic alterations in PolqSL genes and exhibit genomic scars of Pol θ/TMEJ hyperactivity, thereby substantially expanding the subset of human cancers for which Pol θ inhibition represents a promising therapeutic strategy.

Date: 2019
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DOI: 10.1038/s41467-019-12234-1

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