Cisplatin depletes TREX2 and causes Robertsonian translocations as seen in TREX2 knockout cells.
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.
Chen
Ming-Jiu
MJ
Department of Molecular Medicine/Institute of Biotechnology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78245-3207, USA
Dumitrache
Lavinia C
LC
Wangsa
Danny
D
Ma
Sheng-Mei
SM
Padilla-Nash
Hesed
H
Ried
Thomas
T
Hasty
Paul
P
D000970:Antineoplastic Agents / Q000494:pharmacology*; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D002467:Cell Nucleus / Q000187:drug effects / Q000201:enzymology; D002945:Cisplatin / Q000494:pharmacology*; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D005090:Exodeoxyribonucleases / Q000172:deficiency* / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D016685:Mitomycin / Q000494:pharmacology; D010750:Phosphoproteins / Q000172:deficiency* / Q000378:metabolism; D014178:Translocation, Genetic / Q000187:drug effects*
D000970:Antineoplastic Agents; D010750:Phosphoproteins; D016685:Mitomycin; D005090:Exodeoxyribonucleases; C486104:TREX2 protein, human; D002945:Cisplatin