The FEN1 L209P mutation interferes with long-patch base excision repair and induces cellular transformation

Sun, Hanyong; He, Lingfeng; Wu, Huan; Pan, Feiyan; Wu, Xiwei; Zhao, Jie; Hu, Zhigang; Kathera, Chandrasekhar; Li, H; Zheng, Li; Chen, H; Shen, Binghui; Guo, Zhigang

doi:10.1038/onc.2016.188

Cited by 36 publications

(33 citation statements)

References 82 publications

(96 reference statements)

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“…Genomic and protein expression analyses revealed FEN1 as a key biomarker in breast and ovarian epithelial cancers, in which FEN1 overexpression is associated with high grade, high stage, and poor survival (Abdel‐Fatah et al ., ). Our team identified the FEN1 mutation in colorectal cancer cells and evaluated its function in cancer progression (Sun et al ., ). Based on these reports, we speculate that FEN1 could be used as a promising cancer diagnostic biomarker.…”

Section: Discussionmentioning

confidence: 97%

FEN1 promotes tumor progression and confers cisplatin resistance in non-small-cell lung cancer

et al. 2017

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Lung cancer is one of the leading causes of cancer mortality worldwide. The therapeutic effect of chemotherapy is limited due to the resistance of cancer cells, which remains a challenge in cancer therapeutics. In this work, we found that flap endonuclease 1 (FEN1) is overexpressed in lung cancer cells. FEN1 is a major component of the base excision repair pathway for DNA repair systems and plays important roles in maintaining genomic stability through DNA replication and repair. We showed that FEN1 is critical for the rapid proliferation of lung cancer cells. Suppression of FEN1 resulted in decreased DNA replication and accumulation of DNA damage, which subsequently induced apoptosis. Manipulating the amount of FEN1 altered the response of lung cancer cells to chemotherapeutic drugs. A small‐molecule inhibitor (C20) was used to target FEN1 and this enhanced the therapeutic effect of cisplatin. The FEN1 inhibitor significantly suppressed cell proliferation and induced DNA damage in lung cancer cells. In mouse models, the FEN1 inhibitor sensitized lung cancer cells to a DNA damage‐inducing agent and efficiently suppressed cancer progression in combination with cisplatin treatment. Our study suggests that targeting FEN1 may be a novel and efficient strategy for a tumor‐targeting therapy for lung cancer.

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Section: Discussionmentioning

confidence: 97%

FEN1 promotes tumor progression and confers cisplatin resistance in non-small-cell lung cancer

et al. 2017

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“…The cleavage of DNA substrates by FEN1 was determined under the same conditions as those previously published (Guo et al, 2008, Sun et al, 2016). Double flap DNA substrate (a long 5′ flap and a short 3′ falp) has been reported as the best substrate for Flap activity (Finger et al, 2009, Tsutakawa et al, 2011, Kao et al, 2002, Friedrich-Heineken and Hubscher, 2004).…”

Section: Methodsmentioning

confidence: 99%

“…DNA replication efficiency of cells was measured by 3 H incorporation assay (Sun et al, 2016). Briefly, 5 × 10 4 cells were seeded onto a 6-cm dish in Dulbecco's Modified Eagle Medium (DMEM) for 12 h. 3 H-thymidine was added to a final concentration of 1 μCi/mL.…”

Section: Methodsmentioning

confidence: 99%

Targeting DNA Flap Endonuclease 1 to Impede Breast Cancer Progression

et al. 2016

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DNA flap endonuclease 1 (FEN1) plays critical roles in maintaining genome stability and integrity by participating in both DNA replication and repair. Suppression of FEN1 in cells leads to the retardation of DNA replication and accumulation of unrepaired DNA intermediates, resulting in DNA double strand breaks (DSBs) and apoptosis. Therefore, targeting FEN1 could serve as a potent strategy for cancer therapy. In this study, we demonstrated that FEN1 is overexpressed in breast cancers and is essential for rapid proliferation of cancer cells. We showed that manipulating FEN1 levels in cells alters the response of cancer cells to chemotherapeutic drugs. Furthermore, we identified a small molecular compound, SC13 that specifically inhibits FEN1 activity, thereby interfering with DNA replication and repair in vitro and in cells. SC13 suppresses cancer cell proliferation and induces chromosome instability and cytotoxicity in cells. Importantly, SC13 sensitizes cancer cells to DNA damage-inducing therapeutic modalities and impedes cancer progression in a mouse model. These findings could establish a paradigm for the treatment of breast cancer and other cancers as well.

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“…As mentioned above, the mitotic DNA repair function of the endonucleases MUS81-EME1, XPF-ERCC1, SLX1-SLX4 and GEN1, required to promote mitotic DNA synthesis and chromosome disjunction, are essential to inhibit 53BP1 NBs [ 85 , 86 , 97 , 103 ]. Another endonuclease, FEN1, involved in Okazaki fragments processing during replication and in Base Excision Repair, also prevents 53BP1 NBs through its nucleolytic activity [ 120 ]. Besides, cells overexpressing FEN1 or XPG, an endonuclease involved in Nucleotide Excision Repair, accumulate 53BP1 NBs [ 121 ], confirming that endonucleases must be tightly regulated to avoid 53BP1 NBs due to uncontrolled DNA stand breaks.…”

Section: Major Cellular Processes and 53bp1 Nbsmentioning

confidence: 99%

Around and beyond 53BP1 Nuclear Bodies

Fernandez-Vidal

Vignard

Mirey

2017

IJMS

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Within the nucleus, sub-nuclear domains define territories where specific functions occur. Nuclear bodies (NBs) are dynamic structures that concentrate nuclear factors and that can be observed microscopically. Recently, NBs containing the p53 binding protein 1 (53BP1), a key component of the DNA damage response, were defined. Interestingly, 53BP1 NBs are visualized during G1 phase, in daughter cells, while DNA damage was generated in mother cells and not properly processed. Unlike most NBs involved in transcriptional processes, replication has proven to be key for 53BP1 NBs, with replication stress leading to the formation of these large chromatin domains in daughter cells. In this review, we expose the composition and organization of 53BP1 NBs and focus on recent findings regarding their regulation and dynamics. We then concentrate on the importance of the replication stress, examine the relation of 53BP1 NBs with DNA damage and discuss their dysfunction.

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The FEN1 L209P mutation interferes with long-patch base excision repair and induces cellular transformation

Cited by 36 publications

References 82 publications

FEN1 promotes tumor progression and confers cisplatin resistance in non-small-cell lung cancer

FEN1 promotes tumor progression and confers cisplatin resistance in non-small-cell lung cancer

Targeting DNA Flap Endonuclease 1 to Impede Breast Cancer Progression

Around and beyond 53BP1 Nuclear Bodies

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