MMR Apoptosis and Chemotherapy Resistance

In addition to its role in DNA repair, the MMR system seems to signal the presence of DNA damage to the apoptosis-initiating system, which may be why MMR-defective tumour cells tend to have increased resistance to DNA-damaging drugs such as cisplatin (see reviews by Li

(1999) and Jiricny and Nystrom-Lahti (2000)). Treatment of a mixture of MMR-proficient and deficient cells with cisplatin resulted in enrichment of the MMR-deficient population (Fink et al., 1998). Moreover, cisplatin resistance in ovarian cancer recently was reported to be linked to suppression of hMLHl due to hypermethylation in the gene's promoter region (Strathdee et al., 1999).

MMR-deficient cells also resist killing by alkylating agents that methylate DNA guanine-O6 positions. Such alkylations are mutagenic, because these alkylated gua-nines base-pair preferentially with T. MMR-deficient cells are alkylation tolerant: they retain the alkylations, but are not killed by them. The cost of survival, however, is mutagenesis. Treatment of MSH2-knockout mice with agents that methylate DNA guanine-O6 positions failed to induce apoptosis in the small intestine (a prominent response in wild-type animals) (Toft et al., 1999). This MSH2-dependent apoptosis was partially mediated by a p53-dependent pathway.

The apoptosis resistance also carries over to other DNA damaging agents including 6-thioguanine (which becomes incorporated into DNA as a bogus base), cisplatin and topoisomerase blockers. Resistance to these agents is conferred by loss of MSH2, MSH6, MLHl or PMS2 functions (but not by loss of MSH3 function) in several mammalian systems. In addition to loss of apoptotic response, the resistant cells do not exhibit the usual G2/M cell cycle arrest. The components of the MMR system thus appear to have an essential role in the transmission of DNA damage signals (see reviews by Buermeyer et al. (1999) and Li (1999)).

The role of MMR in apoptosis signalling may have relevance for chemotherapy with DNA-damaging agents, because drug resistance may develop by loss of MMR function in a single selection step (Aebi et al., 1996). Loss of MMR may also confer resistance to low doses of ionizing radiation (Fritzell et al., 1997; DeWeese et al., 1998) (see review by Li (1999)).

The route by which signals from the MMR system induce apoptosis remains to be elucidated; it may in part involve phosphorylation of p53 and/or the related p73 family proteins (Duckett et al., 1999; Li, 1999). The function of p73 in the induction of apoptosis in cisplatin-treated cells may be regulated by tyrosine kinase c-Abl (Gong et al., 1999). Since MMR is targeted exclusively to newly synthesized DNA strands (or to strand regions containing nearby strand breaks (Duckett et al., 1999)), base damage in the template strand could not be removed: the MMR system could sense the mismatch caused by the base damage, but would attempt to repair the wrong strand. This futile repair cycle is one model proposed as the initiator of the apoptosis signal. Alternatively, the MMR recognition complex might assemble at damage-induced mismatches near replication forks, block replication and thereby induce apoptosis (Li, 1999).

Thus the MMR system corrects DNA mismatches caused by base damage in newly synthesized DNA strands (or in strands near break sites). However, when presented with damage that it cannot repair, the system sends out an apoptosis-inducing signal. Loss of components of the MMR system allows cells to survive and proliferate while retaining an accumulation of DNA damage. Treatment of MMR-defective tumours with drugs that alkylate DNA at guanine-06 positions may therefore be ineffective or even detrimental (Li, 1999).

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Body Detox Made Easy

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