Both hMutSα and hMutSß DNA mismatch repair complexes participate in 5-fluorouracil cytotoxicity.
Patients with advanced microsatellite unstable colorectal cancers do not show a survival benefit from 5-fluorouracil (5-FU)-based chemotherapy. We and others have shown that the DNA mismatch repair (MMR) complex hMutSα binds 5-FU incorporated into DNA. Although hMutSß is known to interact with inter...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2011-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3229514?pdf=render |
| _version_ | 1811281943811063808 |
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| author | Akihiro Tajima Moriya Iwaizumi Stephanie Tseng-Rogenski Betty L Cabrera John M Carethers |
| author_facet | Akihiro Tajima Moriya Iwaizumi Stephanie Tseng-Rogenski Betty L Cabrera John M Carethers |
| author_sort | Akihiro Tajima |
| collection | DOAJ |
| description | Patients with advanced microsatellite unstable colorectal cancers do not show a survival benefit from 5-fluorouracil (5-FU)-based chemotherapy. We and others have shown that the DNA mismatch repair (MMR) complex hMutSα binds 5-FU incorporated into DNA. Although hMutSß is known to interact with interstrand crosslinks (ICLs) induced by drugs such as cisplatin and psoralen, it has not been demonstrated to interact with 5-FU incorporated into DNA. Our aim was to examine if hMutSß plays a role in 5-FU recognition.We compared the normalized growth of 5-FU treated cells containing either or both mismatch repair complexes using MTT and clonogenic assays. We utilized oligonucleotides containing 5-FU and purified baculovirus-synthesized hMutSα and hMutSß in electromobility shift assays (EMSA) and further analyzed binding using surface plasmon resonance.MTT and clonogenic assays after 5-FU treatment demonstrated the most cytotoxicity in cells with both hMutSα and hMutSß, intermediate cytotoxicity in cells with hMutSα alone, and the least cytotoxicity in cells with hMutSß alone, hMutSß binds 5-FU-modified DNA, but its relative binding is less than the binding of 5-FU-modified DNA by hMutSα.Cytotoxicity induced by 5-FU is dependent on intact DNA MMR, with relative cell death correlating directly with hMutSα and/or hMutSß 5-FU binding ability (hMutSα>hMutSß). The MMR complexes provide a hierarchical chemosensitivity for 5-FU cell death, and may have implications for treatment of patients with certain MMR-deficient tumors. |
| first_indexed | 2024-04-13T01:43:36Z |
| format | Article |
| id | doaj.art-1928a65b249940ccb632c1529d29492d |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-13T01:43:36Z |
| publishDate | 2011-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-1928a65b249940ccb632c1529d29492d2022-12-22T03:08:07ZengPublic Library of Science (PLoS)PLoS ONE1932-62032011-01-01612e2811710.1371/journal.pone.0028117Both hMutSα and hMutSß DNA mismatch repair complexes participate in 5-fluorouracil cytotoxicity.Akihiro TajimaMoriya IwaizumiStephanie Tseng-RogenskiBetty L CabreraJohn M CarethersPatients with advanced microsatellite unstable colorectal cancers do not show a survival benefit from 5-fluorouracil (5-FU)-based chemotherapy. We and others have shown that the DNA mismatch repair (MMR) complex hMutSα binds 5-FU incorporated into DNA. Although hMutSß is known to interact with interstrand crosslinks (ICLs) induced by drugs such as cisplatin and psoralen, it has not been demonstrated to interact with 5-FU incorporated into DNA. Our aim was to examine if hMutSß plays a role in 5-FU recognition.We compared the normalized growth of 5-FU treated cells containing either or both mismatch repair complexes using MTT and clonogenic assays. We utilized oligonucleotides containing 5-FU and purified baculovirus-synthesized hMutSα and hMutSß in electromobility shift assays (EMSA) and further analyzed binding using surface plasmon resonance.MTT and clonogenic assays after 5-FU treatment demonstrated the most cytotoxicity in cells with both hMutSα and hMutSß, intermediate cytotoxicity in cells with hMutSα alone, and the least cytotoxicity in cells with hMutSß alone, hMutSß binds 5-FU-modified DNA, but its relative binding is less than the binding of 5-FU-modified DNA by hMutSα.Cytotoxicity induced by 5-FU is dependent on intact DNA MMR, with relative cell death correlating directly with hMutSα and/or hMutSß 5-FU binding ability (hMutSα>hMutSß). The MMR complexes provide a hierarchical chemosensitivity for 5-FU cell death, and may have implications for treatment of patients with certain MMR-deficient tumors.http://europepmc.org/articles/PMC3229514?pdf=render |
| spellingShingle | Akihiro Tajima Moriya Iwaizumi Stephanie Tseng-Rogenski Betty L Cabrera John M Carethers Both hMutSα and hMutSß DNA mismatch repair complexes participate in 5-fluorouracil cytotoxicity. PLoS ONE |
| title | Both hMutSα and hMutSß DNA mismatch repair complexes participate in 5-fluorouracil cytotoxicity. |
| title_full | Both hMutSα and hMutSß DNA mismatch repair complexes participate in 5-fluorouracil cytotoxicity. |
| title_fullStr | Both hMutSα and hMutSß DNA mismatch repair complexes participate in 5-fluorouracil cytotoxicity. |
| title_full_unstemmed | Both hMutSα and hMutSß DNA mismatch repair complexes participate in 5-fluorouracil cytotoxicity. |
| title_short | Both hMutSα and hMutSß DNA mismatch repair complexes participate in 5-fluorouracil cytotoxicity. |
| title_sort | both hmutsα and hmutsss dna mismatch repair complexes participate in 5 fluorouracil cytotoxicity |
| url | http://europepmc.org/articles/PMC3229514?pdf=render |
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