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      Inhibition of PC4 radiosensitizes non‐small cell lung cancer by transcriptionally suppressing XLF

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          Abstract

          Positive cofactor 4 ( PC4) participates in DNA damage repair and involved in nonhomologous end joining ( NHEJ). Our previous results demonstrated that knockdown of PC4 downregulated the expression of XRCC4‐like factor ( XLF) in esophageal squamous cell carcinoma. However, the mechanism how PC4 regulates the expression of XLF remains unclear. Here, we found that knockdown of PC4 increased radiosensitivity of non‐small cell lung cancer ( NSCLC) both in vivo and in vitro. Furthermore, we found that PC4 knockdown downregulated the expression of XLF, whereas recovering XLF expression restored radioresistance in the PC4‐knockdown NSCLC cells. In addition, PC4 knockdown inhibited XLF expression by transcriptionally suppressing of XLF. Moreover, PC4 expression correlated with radiosensitivity and was an independent prognostic factor of progression‐free survival ( PFS) in patients with NSCLC. These findings suggest that PC4 could be used as a promising therapeutic target for NSCLC.

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          XLF interacts with the XRCC4-DNA ligase IV complex to promote DNA nonhomologous end-joining.

          DNA nonhomologous end-joining (NHEJ) is a predominant pathway of DNA double-strand break repair in mammalian cells, and defects in it cause radiosensitivity at the cellular and whole-organism levels. Central to NHEJ is the protein complex containing DNA Ligase IV and XRCC4. By searching for additional XRCC4-interacting factors, we identified a previously uncharacterized 33 kDa protein, XRCC4-like factor (XLF, also named Cernunnos), that has weak sequence homology with XRCC4 and is predicted to display structural similarity to XRCC4. We show that XLF directly interacts with the XRCC4-Ligase IV complex in vitro and in vivo and that siRNA-mediated downregulation of XLF in human cell lines leads to radiosensitivity and impaired NHEJ. Furthermore, we establish that NHEJ-deficient 2BN cells derived from a radiosensitive and immune-deficient patient lack XLF due to an inactivating frameshift mutation in its gene, and that reintroduction of wild-type XLF into such cells corrects their radiosensitivity and NHEJ defects. XLF thus constitutes a novel core component of the mammalian NHEJ apparatus.
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            Detection and repair of ionizing radiation-induced DNA double strand breaks: new developments in nonhomologous end joining.

            DNA damage can occur as a result of endogenous metabolic reactions and replication stress or from exogenous sources such as radiation therapy and chemotherapy. DNA double strand breaks are the most cytotoxic form of DNA damage, and defects in their repair can result in genome instability, a hallmark of cancer. The major pathway for the repair of ionizing radiation-induced DSBs in human cells is nonhomologous end joining. Here we review recent advances on the mechanism of nonhomologous end joining, as well as new findings on its component proteins and regulation. Copyright © 2013 Elsevier Inc. All rights reserved.
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              Activation of meiosis-specific genes is associated with depolyploidization of human tumor cells following radiation-induced mitotic catastrophe.

              Cancer is frequently characterized histologically by the appearance of large cells that are either aneuploid or polyploid. Aneuploidy and polyploidy are hallmarks of radiation-induced mitotic catastrophe (MC), a common phenomenon occurring in tumor cells with impaired p53 function following exposure to various cytotoxic and genotoxic agents. MC is characterized by altered expression of mitotic regulators, untimely and abnormal cell division, delayed DNA damage, and changes in morphology. We report here that cells undergoing radiation-induced MC are more plastic with regards to ploidy and that this plasticity allows them to reorganize their genetic material through reduction division to produce smaller cells which are morphologically indistinguishable from control cells. Experiments conducted with the large-scale digital cell analysis system are discussed and show that a small fraction of polyploid cancer cells formed via radiation-induced MC can survive and start a process of depolyploidization that yields various outcomes. Although most multipolar divisions failed and cell fusion occurred, some of these divisions were successful and originated a variety of cell progeny characterized by different ploidy. Among these ploidy phenotypes, a progeny of small mononucleated cells, indistinguishable from the untreated control cells, is often seen. We report here evidence that meiosis-specific genes are expressed in the polyploid cells during depolyploidization. Tumor cells might take advantage of the temporary change from a promitotic to a promeiotic division regimen to facilitate depolyploidization and restore the proliferative state of the tumor cell population. These events might be mechanisms by which tumor progression and resistance to treatment occur in vivo.
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                Author and article information

                Contributors
                qiankeyu1984@126.com
                pangqingsongtj@163.com
                wangping@tjmuch.com
                Journal
                Cancer Med
                Cancer Med
                10.1002/(ISSN)2045-7634
                CAM4
                Cancer Medicine
                John Wiley and Sons Inc. (Hoboken )
                2045-7634
                09 March 2018
                April 2018
                : 7
                : 4 ( doiID: 10.1002/cam4.2018.7.issue-4 )
                : 1326-1337
                Affiliations
                [ 1 ] Department of Radiotherapy National Clinical Research Center for Cancer Tianjin's Clinical Research Center for Cancer Key Laboratory of Cancer Prevention and Therapy Tianjin Medical University Cancer Institute and Hospital Tianjin China
                [ 2 ] Department of Radiotherapy Tianjin Hospital Tianjin China
                Author notes
                [*] [* ] Correspondence

                Dong Qian, Qingsong Pang and Ping Wang, Department of Radiotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Huanhu West Road, Tianjin 300060, China. Tel: +86‐022‐23340123; Fax: 022‐23537796; E‐mails: qiankeyu1984@ 123456126.com (D. Q.); pangqingsongtj@ 123456163.com (Q. P.); wangping@ 123456tjmuch.com (P. W.)

                [†]

                These authors contribute equally to this work.

                Author information
                http://orcid.org/0000-0003-0003-8001
                http://orcid.org/0000-0001-9416-2905
                Article
                CAM41332
                10.1002/cam4.1332
                5911594
                29522271
                a7942c12-65e2-49b1-ab1e-a54ce4139ab4
                © 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 27 July 2017
                : 30 November 2017
                : 14 December 2017
                Page count
                Figures: 6, Tables: 2, Pages: 12, Words: 4785
                Funding
                Funded by: National Natural Science Foundation of China
                Award ID: 81372518
                Award ID: 81602565
                Award ID: 81773235
                Award ID: 81401948
                Funded by: Subject of Science and Technology Development Fund of Tianjin Education Commission
                Award ID: 20140111
                Categories
                Original Research
                Cancer Biology
                Original Research
                Custom metadata
                2.0
                cam41332
                April 2018
                Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.3.4 mode:remove_FC converted:23.04.2018

                Oncology & Radiotherapy
                non‐small cell lung cancer,positive cofactor 4,radiosensitivity,transcriptional regulation,xrcc4‐like factor

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