DNA Mismatch Repair and Malaria Drug Resistance

描述(申请人提供)：细胞无法保持基因组的完整性导致DNA突变的快速积累，这是许多疾病的基础。特别是，DNA错配修复(MMR)活性的丧失与几种形式的癌症、微卫星不稳定以及最明显的化疗耐药有关。用作药物治疗的DNA损伤剂通常与MMR活性降低的细胞中的耐药表型有关。许多最常用的抗疟疾药物都是DNA改变剂，可能在疟疾寄生虫耐药表型的选择中发挥关键作用。这种抗性可能与寄生虫内MMR活性的丧失或降低直接相关。考虑到恶性疟原虫抗药性的快速发展及其异常高的富含A-T的基因组(具有突变表型的特征)，不难想象这种寄生虫已经大大降低了复制后修复效率。此外，疟原虫基因组中缺少MSH3和MSH5同源物可能会使某些类型的DNA损伤持续存在，否则这些损伤将通过MMR途径移除。我们的假设是，恶性疟原虫耐药株对错配的DNA底物的修复减少，这种活性降低是疟疾耐药性发展的潜在机制。高效的MMR在确定细胞对DNA改变剂的敏感性方面起着不可或缺的作用。我们进一步假设，目前的抗疟疾药物，其中一些是已知的DNA改变剂，是针对具有降低MMR效率的寄生虫群体进行选择的。因此，我们建议研究MMR在恶性疟原虫耐药性中的作用。人类疟疾是一个巨大的全球健康问题，每年感染3-5亿人，造成1-300万人死亡。了解恶性疟原虫如何维持基因组完整性是疟疾生物学领域的未知领域，可能是阐明这种寄生虫对化疗的非凡适应性的关键。我们的假设是，恶性疟原虫耐药株对错配的DNA底物的修复减少，这种活性降低是疟疾耐药性发展的潜在机制。

DESCRIPTION (provided by applicant): The inability of cells to maintain genomic integrity leads to the rapid accumulation of DNA mutations, a scenario that underlies many diseases. In particular, the ablation of DNA mismatch repair (MMR) activity has been linked to several forms of cancer, microsatellite instability, and most notably chemotherapeutic drug resistance. DNA damaging agents used as drug treatments are often associated with a resistance phenotype in cells with decreased MMR activity. Many of the most commonly used antimalarial drugs are DNA altering agents and may play a critical role in the selection of a drug resistant phenotype within the malaria parasite. This resistance may be directly associated with a loss or decrease of MMR activity within parasites. Given Plasmodium falciparum's rapid development of drug resistance and its unusually high A-T rich genome, characteristic of a mutator phenotype, it is not difficult to imagine that the parasite has greatly diminished post-replication repair efficiency. Moreover, the absence of an MSH3 and MSH5 homologue from the Plasmodium genome may allow the persistence of certain types of DNA lesions that would otherwise be removed by the MMR pathway. It is our hypothesis that P. falciparum drug resistant strains have decreased repair of mispaired DNA substrates and that this decreased activity is the underlying mechanism in the development of malaria drug resistance. Efficient MMR plays an indispensable role in determining cellular sensitivity to DNA altering agents. We further hypothesize that current antimalarial drugs, some of which are known DNA altering agents, are selecting for a population of parasites possessing a decreased MMR efficiency. Therefore, we propose to investigate the role that MMR plays in Plasmodium falciparum drug resistance. PUBLIC HEALTH RELEVANCE Human malaria is an enormous global health problem, infecting 300-500 million people, and causing 1-3 million deaths annually. Understanding how Plasmodium falciparum maintains genomic integrity is uncharted territory within malaria biology and may be the key to elucidating the parasites extraordinary adaptability to chemotherapy. It is our hypothesis that P. falciparum drug resistant strains have decreased repair of mispaired DNA substrates and that this decreased activity is the underlying mechanism in the development of malaria drug resistance.