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ABSTRACT Hypersensitivity of Brca1-deficient cells to interstrand crosslinking (ICL) agents such as cisplatin and mitomycin C (MMC) implicates an important role for Brca1 in cellular

response to the ICL DNA damage repair. However, the detailed mechanism of how Brca1 is involved in the ICL response remains unclear. In this study, we analysed the cellular response to MMC

treatment using isogenic mouse embryonic fibroblasts (MEFs) including wild type, p53−/− and p53−/−Brca1−/−. Marked hypersensitivity of p53−/−Brca1−/− MEFs to MMC was found, and the

reconstitution of Brca1 expression in these cells restored resistance to MMC. Upon MMC treatment, wild-type MEF was temporarily arrested at G2/M phase but subsequently resumed a normal cell

cycle progression. In contrast, Brca1-deficient MEF exhibited a marked time-dependent accumulation of cells arrested at S phase and a prolonged increase in the G2/M population, followed by

extensive cell deaths. Importantly, DNA damage-induced Rad51 foci were not formed in these cells, suggesting a defect in homologous recombination. Such defects are fully rescued by

reconstitution of Brca1 expression in Brca1-deficient MEF, suggesting that Brca1 directly plays an essential role in ICL repair, which depends on homologous recombination during S phase.

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support SIMILAR CONTENT BEING VIEWED BY OTHERS BRCA2-DSS1 INTERACTION IS DISPENSABLE FOR RAD51 RECRUITMENT AT REPLICATION-INDUCED AND MEIOTIC DNA DOUBLE STRAND BREAKS Article Open access 01

April 2022 THE CIP2A–TOPBP1 AXIS SAFEGUARDS CHROMOSOME STABILITY AND IS A SYNTHETIC LETHAL TARGET FOR _BRCA_-MUTATED CANCER Article 11 November 2021 POLΘ-MEDIATED END JOINING IS RESTRICTED

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28641–28647. * Zhong Q, Chen CF, Li S, Chen Y, Wang CC, Xiao J, Chen PL, Sharp ZD and Lee WH . (1999). _Science_, 285, 747–750. Download references ACKNOWLEDGEMENTS We thank Dr Olga

Aprelikova for murine Brca1 expression construct, Dr G Nolan for phoenix ampho cell line for retrovirus production, Diane C Jones for the preparation of anti-murine Brca1 polyclonal

antibodies and Saori Furuta for critical reading of the manuscript. This work was supported by the NIH Grant CA94170 (to WH Lee) and Korea Science and Engineering Foundation through the

Medical Science and Engineering Research Center for Cancer Molecular Therapy at Dong-A University (to J Yun and JY Kwak). AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Medical Research

Center for Cancer Molecular Therapy, College of Medicine, Dong-A University, Busan, 602-714, South Korea Jeanho Yun & Jong-Young Kwak * Department of Biochemistry, College of Medicine,

Dong-A University, Busan, 602-714, South Korea Jeanho Yun & Jong-Young Kwak * Department of Biological Chemistry, School of Medicine, University of California, 124 Sprague Hall, 839

Medical Science Court, Irvine, CA, 92697, USA Qing Zhong & Wen-Hwa Lee Authors * Jeanho Yun View author publications You can also search for this author inPubMed Google Scholar * Qing

Zhong View author publications You can also search for this author inPubMed Google Scholar * Jong-Young Kwak View author publications You can also search for this author inPubMed Google

Scholar * Wen-Hwa Lee View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Wen-Hwa Lee. RIGHTS AND PERMISSIONS Reprints

and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Yun, J., Zhong, Q., Kwak, JY. _et al._ Hypersensitivity of Brca1-deficient MEF to the DNA interstrand crosslinking agent mitomycin C is

associated with defect in homologous recombination repair and aberrant S-phase arrest. _Oncogene_ 24, 4009–4016 (2005). https://doi.org/10.1038/sj.onc.1208575 Download citation * Received:

08 December 2004 * Revised: 08 January 2005 * Accepted: 26 January 2005 * Published: 21 March 2005 * Issue Date: 09 June 2005 * DOI: https://doi.org/10.1038/sj.onc.1208575 SHARE THIS ARTICLE

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Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * Brca1 * mitomycin C * DNA interstrand crosslink (ICL) repair * Rad51 * S phase