Journal
CANCER RESEARCH
Volume 67, Issue 19, Pages 9077-9083Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-07-1146
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Funding
- NCI NIH HHS [T32 CA86800-03, R01 CA123203-01A1] Funding Source: Medline
- NIEHS NIH HHS [U01 ES11044] Funding Source: Medline
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Cisplatin, an anticancer drug, forms DNA interstrand crosslinks (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 lCLs and (b) the depletion of ;TREX2.
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