Cisplatin depletes TREX2 and causes robertsonian translocations as seen in TREX2 knockout cells

Ming Jiu Chen, Lavinia C. Dumitrache, Danny Wangsa, Sheng Mei Ma, Hesed Padilla-Nash, Thomas Ried, Paul Hasty

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

Cisplatin, an anticancer drug, forms DNA interstrand cross-links (ICL) that interfere with replication, whereas TREX2 is a 3′→5′ exonuclease that removes 3′ mismatched nucleotides and promotes cellular proliferation. Here, we show that TREX2 is depleted in human cells derived from cancer after exposure to cisplatin but not other genotoxins including another cross-linking agent, mitomycin C (MMC), indicating a potential role for TREX2 depletion in cisplatin-induced cytotoxicity. To better understand TREX2 cellular function, we deleted TREX2 in mouse embryonic stem (ES) cells by gene targeting and find these cells exhibit reduced proliferation and gross chromosomal rearrangements including Robertsonian translocations (RbT). Quite interestingly, ES cells exposed to cisplatin also exhibit RbTs. By contrast, RbTs are not observed for ES cells exposed to MMC, indicating that RbTs are not caused by ICLs but instead TREX2 depletion by either cisplatin exposure or mutation. Taken together, our results show that cisplatin depletes TREX2 and causes genomic instability that is similarly observed in TREX2-mutant cells. Thus, cisplatin has two potential cytotoxic activities: (a) the generation of ICLs and (b) the depletion of TREX2.

Original languageEnglish (US)
Pages (from-to)9077-9083
Number of pages7
JournalCancer Research
Volume67
Issue number19
DOIs
StatePublished - Oct 1 2007

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Chen, M. J., Dumitrache, L. C., Wangsa, D., Ma, S. M., Padilla-Nash, H., Ried, T., & Hasty, P. (2007). Cisplatin depletes TREX2 and causes robertsonian translocations as seen in TREX2 knockout cells. Cancer Research, 67(19), 9077-9083. https://doi.org/10.1158/0008-5472.CAN-07-1146