Rhodium metalloinsertor binding generates a lesion with selective cytotoxicity for mismatch repair-deficient cells.
Proc Natl Acad Sci U S A
; 114(27): 6948-6953, 2017 07 03.
Article
em En
| MEDLINE
| ID: mdl-28634291
ABSTRACT
The DNA mismatch repair (MMR) pathway recognizes and repairs errors in base pairing and acts to maintain genome stability. Cancers that have lost MMR function are common and comprise an important clinical subtype that is resistant to many standard of care chemotherapeutics such as cisplatin. We have identified a family of rhodium metalloinsertors that bind DNA mismatches with high specificity and are preferentially cytotoxic to MMR-deficient cells. Here, we characterize the cellular mechanism of action of the most potent and selective complex in this family, [Rh(chrysi)(phen)(PPO)]2+ (Rh-PPO). We find that Rh-PPO binding induces a lesion that triggers the DNA damage response (DDR). DDR activation results in cell-cycle blockade and inhibition of DNA replication and transcription. Significantly, the lesion induced by Rh-PPO is not repaired in MMR-deficient cells, resulting in selective cytotoxicity. The Rh-PPO mechanism is reminiscent of DNA repair enzymes that displace mismatched bases, and is differentiated from other DNA-targeted chemotherapeutics such as cisplatin by its potency, cellular mechanism, and selectivity for MMR-deficient cells.
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Base de dados:
MEDLINE
Assunto principal:
Ródio
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Dano ao DNA
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DNA
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Ciclo Celular
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Citotoxinas
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Reparo de Erro de Pareamento de DNA
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Complexos de Coordenação
Limite:
Humans
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article