Targeting DNA Double-Strand Break (DSB) Repair to Counteract Tumor Radio-resistance

Abstract

During the last decade, advances of radiotherapy (RT) have been made in the clinical practice of cancer treatment. RT exerts its anticancer effect mainly via leading to the DNA Double-Strand Break (DSB), which is one of the most toxic DNA damages. Non-Homologous End Joining (NHEJ) and Homologous Recombination (HR) are two major DSB repair pathways in human cells. It is known that dysregulations of DSB repair elicit a predisposition to cancer and probably result in resistance to cancer therapies including RT. Therefore, targeting the DSB repair presents an attractive strategy to counteract radio-resistance. In this review, we describe the latest knowledge of the two DSB repair pathways, focusing on several key proteins contributing to the repair, such as DNA-PKcs, RAD51, MRN and PARP1. Most importantly, we discuss the possibility of overcoming radiation resistance by targeting these proteins for therapeutic inhibition. Recent tests of DSB repair inhibitors in the laboratory and their translations into clinical studies are also addressed.

Therapeutic Strategies Targeting Cancer Stem Cells and Their Microenvironment

“…In nasopharyngeal and gastric cancer, MRN-ATM meditated DNA repair induced resistance to common chemotherapy agents, such as cisplatin and 5-FU (113, 114). The MRN complex also acts as one of the DSB pathway key elements to produce radio-resistance in various cancer types (115). Transcription factors such as forkhead box protein m1 (FOXM1), P53, glioma-associated oncogene (GLI1), and c-MYC, were also shown to be important for the DNA repair response (116, 117).…”

DNA Repair Genes as Drug Candidates for Early Breast Cancer Onset in Latin America: A Systematic Review

“…Studies have shown multiple altered variants in DNA repair genes implied in BC predisposition, development, and outcome [ 11 , 12 , 13 , 14 ], including BRCA and non-BRCA genes. Among these, pathogenic variants in the high penetrance BRCA1/2 genes account for 50–60% and the remaining variants, to non-BRCA genes of moderate and low penetrance, including ATM , PALB2 , RAD51 , and BARD1 , all involved in double-strand break repair pathways [ 15 , 16 , 17 , 18 , 19 , 20 , 21 ]. For this reason, it is relevant to elucidate the mechanisms of DNA repair genes in BC, using different approaches such as in silico, in vitro, and in vivo models.…”

Thymine DNA glycosylase‐regulated TAZ promotes radioresistance by targeting nonhomologous end joining and tumor progression in esophageal cancer

“…The dysregulated double‐strand break (DSB) repair is a principal cause of radioresistance, and NHEJ is its most crucial mechanism 21 . To elucidate the association between TAZ and DSB repair, we examined the dynamic levels of γ‐H2AX, a hallmark of DSB, post‐irradiation.…”