Role of Paralogue of XRCC4 and XLF in DNA Damage Repair and Cancer Development.

Jialin Tang,Weili Li,Zhongxia Li,Qiong Wu,Xiangyu Liu,Muhammad Irfan

doi:10.3389/fimmu.2022.852453

Abstract

Non-homologous end joining (cNHEJ) is a major pathway to repair double-strand breaks (DSBs) in DNA. Several core cNHEJ are involved in the progress of the repair such as KU70 and 80, DNA-dependent protein kinase catalytic subunit (DNA-PKcs), Artemis, X-ray repair cross-complementing protein 4 (XRCC4), DNA ligase IV, and XRCC4-like factor (XLF). Recent studies have added a number of new proteins during cNHEJ. One of the newly identified proteins is Paralogue of XRCC4 and XLF (PAXX), which acts as a scaffold that is required to stabilize the KU70/80 heterodimer at DSBs sites and promotes the assembly and/or stability of the cNHEJ machinery. PAXX plays an essential role in lymphocyte development in XLF-deficient background, while XLF/PAXX double-deficient mouse embryo died before birth. Emerging evidence also shows a connection between the expression levels of PAXX and cancer development in human patients, indicating a prognosis role of the protein. This review will summarize and discuss the function of PAXX in DSBs repair and its potential role in cancer development.

Highlights

DNA double-strand breaks (DSBs) create harmful lesions that are typically generated in response to extrinsic sources like ionizing radiation (IR) and chemotherapeutic drugs or intrinsic sources such as DNA replication fork collapse, transcription, and oxidative stress
Overexpression of Paralogue of XRCC4 and XLF (PAXX) was not able to rescue the end-ligation defects in XRCC4-like factor (XLF)-deficient cells with ATM inhibition [47]. All these results indicate that PAXX has distinct functions with XLF in classical non-homologous end-joining (cNHEJ), and PAXX and XLF may synergistically regulate cNHEJ in different mechanisms
PAXX stimulates the ligation of non-cohesive DNA ends in the presence of XLF [33]. These results suggest that PAXX is more likely an accessory factor that associates with KU, and its function in cNHEJ is redundant with XLF [38]

Summary

Introduction

DNA double-strand breaks (DSBs) create harmful lesions that are typically generated in response to extrinsic sources like ionizing radiation (IR) and chemotherapeutic drugs or intrinsic sources such as DNA replication fork collapse, transcription, and oxidative stress. Given the importance of this new cNHEJ factor, we will discuss the role of PAXX in DNA repair and its biological functions in lymphocyte development and tumorigenesis in this review. After 24 h recovery, similar to Lig4−/− control, Xlf−/−Paxx−/− pre-B cells showed persistent gH2AX foci compared with WT or single-deficient cells, implying that PAXX/XLF double deficiency, instead of single deficiency of each protein, blocked repair of genotoxic DSBs [49].

Results

Conclusion