1. Cisplatin is a chemotherapy drug. It was the first member of a class of platinum-containing anti-cancer drugs. These platinum complexes react in the body, binding to DNA and causing the DNA strands to cross-link, which ultimately triggers cells to die by apoptosis.
Cisplatin can create intra-strand (within a strand) cross-links with purine bases, which are readily excised by the nucleotide excision repair (NER). But cisplatin also creates inter-strand (between strands) crosslinks and these are essential to its activity as chemotherapeutic agent. In humans, the leading cause of cancer deaths worldwide is lung cancer, including non small cell lung carcinoma (NSLC) which accounts for 85% of all lung cancer cases in the United States. Individuals with NSLC are often treated with therapeutic platinum compounds such as cisplatin that cause inter-strand DNA crosslinks. In individuals with NSLC, low expression of BRCA1 in the primary tumor correlated with improved survival after platinum-containing chemotherapy. This correlation implies that low BRCA1 in the cancer, and the consequent low level of DNA repair, causes vulnerability of the cancer to treatment by the DNA cross-linking agents.
(a) How could intra-strand (within a strand) cross-links be repaired by nucleotide excision repair? Be sure to note the key steps.
(b) How could inter-strand (between strands of DNA) cross-links be repaired by nucleotide excision repair? Be sure to note the key steps.
(c) Which type of DNA repair processes typically require BRCA1?
(d) Why might low levels of BRCA1 lead to a better outcome in the treatment of NSLC with cisplatin?
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