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XRCC4, which is inhibited by PFDA, regulates DNA damage repair and cell chemosensitivity
Author(s) -
Liu Fengyan,
Fan Ziyan,
Song Ning,
Han Mingyong,
Yan Ming,
Guo LiangHong,
Jihui Jia,
Liu Shili
Publication year - 2019
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.28534
Subject(s) - dna repair protein xrcc4 , dna damage , dna repair , genotoxicity , apoptosis , biology , cell culture , microbiology and biotechnology , dna , cancer research , chemistry , nucleotide excision repair , genetics , toxicity , organic chemistry
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.