%A Trenner,Anika %A Sartori,Alessandro A. %D 2019 %J Frontiers in Oncology %C %F %G English %K homologous recombination (HR),BRCA,Alternative end joining (A-EJ),PARP inhibition,DNA polymerase theta,synthetic lethality,DSB repair,cancer therapy %Q %R 10.3389/fonc.2019.01388 %W %L %M %P %7 %8 2019-December-10 %9 Mini Review %# %! Targeting DNA double-strand break repair %* %< %T Harnessing DNA Double-Strand Break Repair for Cancer Treatment %U https://www.frontiersin.org/articles/10.3389/fonc.2019.01388 %V 9 %0 JOURNAL ARTICLE %@ 2234-943X %X DNA double-strand breaks (DSBs) are highly deleterious, with a single unrepaired DSB being sufficient to trigger cell death. Compared to healthy cells, cancer cells have a higher DSB burden due to oncogene-induced replication stress and acquired defects in DNA damage response (DDR) mechanisms. Consequently, hyperproliferating cancer cells rely on efficient DSB repair for their survival. Moreover, augmented DSB repair capacity is a major cause of radio- and chemoresistance and, ultimately, cancer recurrence. Although inherited DDR defects can predispose individuals to develop certain cancers, the very same vulnerability may be therapeutically exploited to preferentially kill tumor cells. A paradigm for DNA repair targeted therapy has emerged in cancers that exhibit mutations in BRCA1 or BRCA2 tumor suppressor genes, conferring a strong defect in homologous recombination, a major and error-free DSB repair pathway. Clinical validation of such approaches, commonly described as synthetic lethality (SL), has been provided by the regulatory approval of poly(ADP-ribose) polymerase 1 inhibitors (PARPi) as monotherapy for BRCA1/2-mutated breast and ovarian tumors. In this review, we will describe the different DSB repair mechanisms and discuss how their specific features could be exploited for cancer therapy. A major emphasis is put on advances in combinatorial treatment modalities and SL approaches arising from DSB repair pathway interdependencies.