A recessive variant of <i>XRCC4</i> predisposes to non-<i>BRCA1/2</i> breast cancer in chinese women and impairs the DNA damage response via dysregulated nuclear localization

He, Min; Hu, Xin; Chen, Li; Cao, A-Yong; Yu, Ke-Da; Shi, Tingyan; Kuang, Xiaying; Shi, Wei; Ling, Hong; Li, Shan; Qiao, Feng; Yao, Ling; Wei, Qingyi; Di, Gen-Hong; Shao, Zhi‐Ming

doi:10.18632/oncotarget.2623

Cited by 5 publications

(5 citation statements)

References 45 publications

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“…This suggests that XRCC4 expression (including decreasing protein caused by structure change) might involve in tumor progression and angiogenesis. Supporting our findings, recent several studies have displayed that structure change and followed expression change impairs the DNA damage response via dysregulated nuclear localization and can promote carcinogenesis of some tumors such as hepatocarcinoma and breast cancer [ 20 , 21 , 24 ].…”

Section: Discussionsupporting

confidence: 89%

“…Considering that recent two studies have shown that the genic mutation at codon 247 (Ala to Ser, rs3734091) of XRCC4 affects the protein location [ 24 ] and hepatocarcinoma prognosis [ 20 ], we investigated whether this mutation correlated with XRCC4 expression (Table 5 ). Higher expression of XRCC4 was detected in the cancerous tissues from hepatocarcinoma patients with wild type of XRCC4 codon 247.…”

Section: Resultsmentioning

confidence: 99%

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Prognostic significance of XRCC4 expression in hepatocellular carcinoma

et al. 2017

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BackgroundOur previous investigations have shown that the variants of X-ray repair complementing 4 (XRCC4) may be involved in hepatocellular carcinoma (hepatocarcinoma) tumorigenesis. This study aimed to investigate the possible prognostic significance of XRCC4 expression for hepatocarcinoma patients and possible value for the selection of transarterial chemoembolization (TACE) treatment.Materials and MethodsWe conducted a hospital-based retrospective analysis (including 421 hepatocarcinoma cases) to analyze the effects of XRCC4 on hepatocarcinoma prognosis and TACE. The levels of XRCC4 expression were tested using immunohistochemistry. The sensitivity of cancer cells to anti-cancer drug doxorubicin was evaluated using the half-maximal inhibitory concentration (IC50).ResultsXRCC4 expression was significantly correlated with pathological features including tumor stage, liver cirrhosis, and micro-vessel density. XRCC4 expression was an independent prognostic factor of hepatocarcinoma, and TACE treatments had no effects on prognosis of hepatocarcinoma patients with high XRCC4 expression. More intriguingly, TACE improved the prognosis of hepatocarcinoma patients with low XRCC4 expression. Functionally, XRCC4 overexpression increased while XRCC4 knockdown reduced the IC50 of cancer cells to doxorubicin.ConclusionsThese results suggest that XRCC4 may be an independent prognostic factor for hepatocarcinoma patients, and that decreasing XRCC4 expression may be beneficial for post-operative adjuvant TACE treatment in hepatocarcinoma.

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Section: Discussionsupporting

confidence: 89%

Section: Resultsmentioning

confidence: 99%

Prognostic significance of XRCC4 expression in hepatocellular carcinoma

et al. 2017

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“…The XRCC4 intronic polymorphism T1394G (SNP rs2075685) is associated with increased breast, oral, and pancreatic cancer incidence [ 111 , 135 , 136 , 137 , 138 ]. The recessive missense XRCC4 polymorphism at codon 247 (c.739G>T, pAla247Ser) (SNP rs3734091) is associated with development of oral cancer, HCC, and breast cancer, in particular increasing the risk of developing triple-negative breast cancer [ 139 , 140 , 141 ]. This mutation disrupts XRCC4 nuclear localization and results in reduced DSB repair, increased IR sensitivity, and genomic instability, and has been shown to be associated with an increased risk of metastasis [ 140 , 141 ].…”

Section: Core Nhej Factors In Carcinogenesis and Cancermentioning

confidence: 99%

“…The recessive missense XRCC4 polymorphism at codon 247 (c.739G>T, pAla247Ser) (SNP rs3734091) is associated with development of oral cancer, HCC, and breast cancer, in particular increasing the risk of developing triple-negative breast cancer [ 139 , 140 , 141 ]. This mutation disrupts XRCC4 nuclear localization and results in reduced DSB repair, increased IR sensitivity, and genomic instability, and has been shown to be associated with an increased risk of metastasis [ 140 , 141 ]. XRCC4 D allele polymorphism (SNP rs28360071) is associated with oral cancer, and this polymorphism was found to be significantly associated with cancer risk in a meta-analysis [ 142 , 143 ].…”

Section: Core Nhej Factors In Carcinogenesis and Cancermentioning

confidence: 99%

The Role of the Core Non-Homologous End Joining Factors in Carcinogenesis and Cancer

Sishc

Davis

2017

Cancers

139

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DNA double-strand breaks (DSBs) are deleterious DNA lesions that if left unrepaired or are misrepaired, potentially result in chromosomal aberrations, known drivers of carcinogenesis. Pathways that direct the repair of DSBs are traditionally believed to be guardians of the genome as they protect cells from genomic instability. The prominent DSB repair pathway in human cells is the non-homologous end joining (NHEJ) pathway, which mediates template-independent re-ligation of the broken DNA molecule and is active in all phases of the cell cycle. Its role as a guardian of the genome is supported by the fact that defects in NHEJ lead to increased sensitivity to agents that induce DSBs and an increased frequency of chromosomal aberrations. Conversely, evidence from tumors and tumor cell lines has emerged that NHEJ also promotes chromosomal aberrations and genomic instability, particularly in cells that have a defect in one of the other DSB repair pathways. Collectively, the data present a conundrum: how can a single pathway both suppress and promote carcinogenesis? In this review, we will examine NHEJ’s role as both a guardian and a disruptor of the genome and explain how underlying genetic context not only dictates whether NHEJ promotes or suppresses carcinogenesis, but also how it alters the response of tumors to conventional therapeutics.

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“…XRCC4 silencing increases the radiosensitivity of various cancer cells in humans, including breast, colon, and lung cancers [ 23 , 24 , 25 ]. Further, genetic variants such as the single nucleotide polymorphism p.Ala247Ser, and other XRCC4 mutations, contribute to cancer susceptibility in non‐ BRCA1/2 breast cancer, oral cancer, and hepatocellular carcinoma in humans [ 26 , 27 , 28 ]. XRCC4 is also the causative gene of human microcephalic primordial dwarfism (MPD), and various XRCC4 mutations have been observed in MPD patients without any overt immunodeficiency [ 29 , 30 ].…”

mentioning

confidence: 99%

Feline XRCC4 undergoes rapid Ku‐dependent recruitment to DNA damage sites

2022

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Radiation and chemotherapy resistance remain some of the greatest challenges in human and veterinary cancer therapies. XRCC4, an essential molecule for nonhomologous end joining repair, is a promising target for radiosensitizers. Genetic variants and mutations of XRCC4 contribute to cancer susceptibility, and XRCC4 is also the causative gene of microcephalic primordial dwarfism (MPD) in humans. The development of clinically effective molecular‐targeted drugs requires accurate understanding of the functions and regulatory mechanisms of XRCC4. In this study, we cloned and sequenced the cDNA of feline XRCC4. Comparative analysis indicated that sequences and post‐translational modification sites that are predicted to be involved in regulating the localization of human XRCC4, including the nuclear localization signal, are mostly conserved in feline XRCC4. All examined target amino acids responsible for human MPD are completely conserved in feline XRCC4. Furthermore, we found that the localization of feline XRCC4 dynamically changes during the cell cycle. Soon after irradiation, feline XRCC4 accumulated at laser‐induced DNA double‐strand break (DSB) sites in both the interphase and mitotic phase, and this accumulation was dependent on the presence of Ku. Additionally, XRCC4 superfamily proteins XLF and PAXX accumulated at the DSB sites. Collectively, these findings suggest that mechanisms regulating the spatiotemporal localization of XRCC4 are crucial for XRCC4 function in humans and cats. Our findings contribute to elucidating the functions of XRCC4 and the role of abnormal XRCC4 in diseases, including cancers and MPD, and may help in developing XRCC4‐targeted drugs, such as radiosensitizers, for humans and cats.

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A recessive variant of XRCC4 predisposes to non-BRCA1/2 breast cancer in chinese women and impairs the DNA damage response via dysregulated nuclear localization

Cited by 5 publications

References 45 publications

Prognostic significance of XRCC4 expression in hepatocellular carcinoma

Prognostic significance of XRCC4 expression in hepatocellular carcinoma

The Role of the Core Non-Homologous End Joining Factors in Carcinogenesis and Cancer

Feline XRCC4 undergoes rapid Ku‐dependent recruitment to DNA damage sites

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