Involvement of classic and alternative non-homologous end joining pathways in hematologic malignancies: targeting strategies for treatment

Mohsen Valikhani,Elahe Rahimian,Rouzbeh Chegeni,Seyed Esmaeil Ahmadi,Majid Safa

doi:10.1186/s40164-021-00242-1

Abstract

Chromosomal translocations are the main etiological factor of hematologic malignancies. These translocations are generally the consequence of aberrant DNA double-strand break (DSB) repair. DSBs arise either exogenously or endogenously in cells and are repaired by major pathways, including non-homologous end-joining (NHEJ), homologous recombination (HR), and other minor pathways such as alternative end-joining (A-EJ). Therefore, defective NHEJ, HR, or A-EJ pathways force hematopoietic cells toward tumorigenesis. As some components of these repair pathways are overactivated in various tumor entities, targeting these pathways in cancer cells can sensitize them, especially resistant clones, to radiation or chemotherapy agents. However, targeted therapy-based studies are currently underway in this area, and furtherly there are some biological pitfalls, clinical issues, and limitations related to these targeted therapies, which need to be considered. This review aimed to investigate the alteration of DNA repair elements of C-NHEJ and A-EJ in hematologic malignancies and evaluate the potential targeted therapies against these pathways.

Highlights

There are different types of DNA damage including Bulky adducts/intrastrand crosslinks, single-strand break, DNA double-strand break (DSB), and base mismatch (Fig. 1)
While recognition of DNA ends by C-non-homologous end-joining (NHEJ) pathways is dependent on XRCC5, XRCC6, DNA-PKcs, and ligation by DNA ligase IV (Lig IV)/XRCC4, the alternative end-joining (A-EJ) pathways are independent of Lig IV and can recognize DNA ends by a diverse set of factors, including different DNA polymerases (δ and θ), Valikhani et al Exp Hematol Oncol (2021) 10:51
Conclusion and future prospects Components of DSB repair (DSBR) pathways are the guards of genome integrity

Summary

Introduction

There are different types of DNA damage including Bulky adducts/intrastrand crosslinks, single-strand break, DNA double-strand break (DSB), and base mismatch (Fig. 1). DSBs are the most destructive genomic damages [1, 2], that may arise either exogenously or endogenously. While the exogenous sources of DSBs include ionizing radiation and DNA damaging agents (clastogens), the endogenous sources commonly result from damages during replication, which, if unrepaired, can stimulate genomic instability [3, 4]. While recognition of DNA ends by C-NHEJ pathways is dependent on XRCC5, XRCC6, DNA-PKcs, and ligation by DNA ligase IV (Lig IV)/XRCC4, the A-EJ pathways are independent of Lig IV and can recognize DNA ends by a diverse set of factors, including different DNA polymerases (δ and θ), Valikhani et al Exp Hematol Oncol (2021) 10:51

Objectives

Findings

Conclusion