Understanding the Molecular Mechanisms and Potential Treatment Options for Cancer Patients with Defects in the Nucleotide Excision DNA Repair Pathway

Abstract

Nucleotide Excision Repair (NER) is among the six repair pathways that maintain the integrity of DNA. A disease known as Xeroderma pigmentosum (XP) is a caused by mutations in genes of the nucleotide excision repair pathway and is characterized by hypersensitivity to sunlight and a high incidence of skin and mucosal cancers. This hypersensitivity arises because unrepaired DNA adducts cause mutations and ultimately cancer develops. Patients with the disease have a 10,000 fold-increased chance of developing cancers compared to the general population. One objective of this research was to characterize mutations found in XP patients to determine the severity of the deficiencies in NER and to characterize the defects at a molecular level. Heterozygous carriers of mutant NER alleles also show increased chance of developing cancer. This is thought to be because of the acquisition of secondary mutations leading to loss of heterozygosity. Such cells experience increased mutation rates and serve as the precursors to cancer. Because these cells are homozygous for the mutant allele, while the other cells in the body are not, the use of chemical synthetic lethality to treat these types of cancers is a viable approach. Exploiting yeast’s ease of genetic manipulation, rapid growth, and high conservation with human DNA repair pathways, we screened for chemicals that cause synthetic lethality in a NER defective background. Overall, NER defective cells are very promising targets for therapeutics. We found that most of the XPA disease allele’s defects arise from reduced protein levels, and that this defect can be reversed by inhibiting the proteasome. For NER deficient cells, it appears that treatment can be achieved by overwhelming or undermining the backup DNA repair pathways that are needed for survival in the absence of NER.