Defining the mutation signatures of DNA polymerase θ in cancer genomes.

Taejoo Hwang,Yoko Takata,John P Murnane,Yerkin Dunbayev,Kevin M Mcbride,Semin Lee,Jong Bhak,Shelley Reh,Jianjun Shen,Richard D Wood,Kei-Ichi Takata,Yi Zhong

doi:10.1093/narcan/zcaa017

Abstract

DNA polymerase theta (POLQ)-mediated end joining (TMEJ) is a distinct pathway for mediating DNA double-strand break (DSB) repair. TMEJ is required for the viability of BRCA-mutated cancer cells. It is crucial to identify tumors that rely on POLQ activity for DSB repair, because such tumors are defective in other DSB repair pathways and have predicted sensitivity to POLQ inhibition and to cancer therapies that produce DSBs. We define here the POLQ-associated mutation signatures in human cancers, characterized by short insertions and deletions in a specific range of microhomologies. By analyzing 82 COSMIC (Catalogue of Somatic Mutations in Cancer) signatures, we found that BRCA-mutated cancers with a higher level of POLQ expression have a greatly enhanced representation of the small insertion and deletion signature 6, as well as single base substitution signature 3. Using human cancer cells with disruptions of POLQ, we further show that TMEJ dominates end joining of two separated DSBs (distal EJ). Templated insertions with microhomology are enriched in POLQ-dependent distal EJ. The use of this signature analysis will aid in identifying tumors relying on POLQ activity.

Highlights

DNA double-strand breaks (DSBs) are deleterious lesions that can lead to cell death if not repaired
substitution signature 3 (SBS3), ID6 and ID8 are enriched in BRCA-mutated cancers expressing high levels of wild-type POLQ
The proportion of SBS3 [a recently updated version 3 signature related to COSMIC3, a version 2 signature [17]] was enriched to 54% in the wild-type POLQ highexpression group in BRCA-mutated cancers (Figure 2A)

Summary

Introduction

DNA double-strand breaks (DSBs) are deleterious lesions that can lead to cell death if not repaired. There are three major pathways for repair of DSBs: (i) nonhomologous end joining (NHEJ), (ii) homologous recombination (HR) and (iii) DNA polymerase theta (␪)-mediated end joining (TMEJ; Figure 1). In the absence of NHEJ, the broken ends are resected by nucleases and the exposed single-stranded DNA (ssDNA) tails are processed by HR or TMEJ. HR uses an undamaged homologous DNA template to repair DNA initiated from ssDNA tails, as does the related single-strand annealing (SSA) process [1,3]. Tumors with disrupted HR or NHEJ pathways, including BRCA1/2, rely on POLQ activity for DSB repair, and are sensitive to POLQ inhibition, PARP inhibition or cancer therapies introducing DSBs [7,8,9]. There is an urgent need to have a general method to identify tumors that rely on POLQ activity

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Conclusion