XRCC4, which is inhibited by PFDA, regulates DNA damage repair and cell chemosensitivity

Abstract

The mechanism of environmental pollution promoting gastric cancer incidence and difficulty of treatment is not fully understood. In the present article, perfluorodecanoic acid (PFDA), a common persistent environmental pollutant, was used to treat the gastric cell lines and mice to test its genotoxicity. The γ-H2AX immunoblot and plasmid fragment PCR results showed that PFDA had a promotion effect on the DNA double-strand breaks (DSBs) in human and mouse cells. Subsequent results showed that PFDA significantly altered the sensitivity of cells to chemotherapy. Microarray data showed that the expressions of some important DNA repair genes were changed. Further investigation discovered that PFDA inhibition of DNA repair was mediated by X-ray repair cross complementing 4 (XRCC4). The cells deficient in XRCC4 generally exhibited reduced proliferation and premature aging in culture; however, our results indicated that PFDA induced p53 inhibition rescued cells from the apoptosis that was triggered by nonhomologous end-joining (NHEJ) inactivation, and overexpression of p53 expression in PFDA-treated cells enhanced their apoptosis. Finally, T-cell specific factor 4 was suggested by the results as an upstream regulator of XRCC4. This article revealed for the first time that perfluorinated chemicals affect chemotherapeutic sensitivity and the NHEJ pathway, and p53 reduction rescues cells from death. K E Y W O R D S chemotherapeutic sensitivity, DNA double-strand breaks (DSBs), p53, perfluorodecanoic acid (PFDA), X-ray repair cross complementing 4 (XRCC4)

X-Ray Repair Cross Complementing 4 (XRCC4) Genetic Single Nucleotide Polymorphisms and the Liver Toxicity of AFB1 in Hepatocellular Carcinoma

“…Normally, XRCC4 is mainly expressed in genital meatus, alimentary tract, and lymphoid tissue; however, its expression will noticeably increase in other tissues such as the skin and liver under the condition of in vitro and in vivo injuries. This gene's encoding protein plays a vital role in both NHEJ and the completion of V(D)J recombination via acting as a scaffold protein for DNA ligase IV and DNA-PK in the repair of DNA DSBs [15,19]. Mutations in XRCC4, including GSNPs and other non-GSNPs variants, can cause endocrine dysfunction, microcephaly, short stature, and diseases [16,21].…”

“…X-ray repair cross complementing 4 (XRCC4), an important DNA repair gene involved in nonhomologous end-joining (NHEJ) repair pathway, plays a scaffold function via stabilizing and localizing DNA repair enzymes LIG IV, Ku70/80 heterodimer, and the DNA-dependent protein kinase (DNA-PK) catalytic subunit (DNA-PKcs) in the ends of DNA double-stranded breaks (DSBs) during NHEJ [15,16]. In the past decades, growing reports have exhibited that the abnormal structures and functions of XRCC4 may alter the capacity of DNA repair and ultimately result in human diseases [17][18][19][20][21][22]. Several recent studies have also shown that the genetic alterations in the coding regions of XRCC4 can modify hepatocellular carcinoma (HCC) risk and prognosis [23][24][25][26][27].…”

Recent Advances in the Development of Non-PIKKs Targeting Small Molecule Inhibitors of DNA Double-Strand Break Repair

“…Early attempts to inhibit XRCC4 resulted in the development of compounds salvianolic acid B, lithospermic acid, and 2- O -feruloyl tartaric acid ( Figure 7 ); however, potential in vitro and in vivo effects of these agents is not documented to date ( 116 ). Recently, Liu et al identified perfluorodecanoic acid (PFDA), a common persistent environmental pollutant, as a XRCC4 inhibitor which was able to sensitize gastric cancer cells to chemotherapy; however, mechanism of action, target engagement with XRCC4 and the toxicity profile of the inhibitor needed to be explored in more details ( 117 ).…”

Druggable binding sites in the multicomponent assemblies that characterise DNA double-strand-break repair through non-homologous end joining

“…However, these studies are rather preliminary and the potential effect of these agents needs to be tested in vitro and subsequently in vivo [ 89 ]. A recent study also reported that perfluorodecanoic acid (PFDA) targeting XRCC4 was able sensitise gastric adenocarcinoma cell lines to chemotherapy, but such targeting was on the mRNA expression level rather than targeting the protein as on all the examples above [ 90 ].…”