INTRODUCTION

Our laboratory studies the biophysical chemistry and genetics of DNA repair. DNA damage processes continually assault the genome of all organisms. Cellular organisms contain multiple, and often redundant, pathways to repair DNA damage. Nearly all of these pathways have been conserved throughout evolution¹.

Chemical and physical damage that results in nucleotide disintegration, nucleotide modification, mismatched nucleotides, and DNA double-stranded breaks (DSB) ultimately contribute to cancer and/or to the genomic breakdown associated with aging. DNA Repair Pathways come in several flavors:

1. Base Excision Repair (BER)
2. Nucleotide Excision Repair (NER)
3. Mismatch Repair (MMR)
4. Recombination Repair (RR).

In general, BER, NER and MMR are non-mutagenic. These repair processes fix the damage without introducing any anomalous sequences to the DNA. There are several pathways of recombination repair. Homologous recombination (HR) uses homologous sequences from a sister or homologous chromosome to repair and/or replace the damaged strand(s) or to seal a double-strand break (DSB). HR is also generally non-mutagenic. Non-homologous end-joining (NHEJ) either directly ligates broken ends or anneals overlapping frayed ends of a DSB. This process is inherently mutagenic and may also contribute to translocations between chromosomes.

Mutations are the cause of cancer. These mutations may be subtle nucleotide changes or gross chromosomal alterations and translocations. Remarkably, the number of mutations in human tumors is enormous – estimated to be between 5 and 15. This is far too high to be accounted by spontaneous mutation. These observations led Loeb to suggest in 1991 that an early mutation in the genes involved in maintaining genomic integrity (DNA repair, replication fidelity, chromosome segregation) would increase the mutation rates; aggravating and accelerating the cancer process. This was termed the Mutator Hypothesis.

In 1993 our laboratory provided substantial support for the Mutator Hypothesis when we showed that mutations in human MMR genes were responsible for what is arguably the most common cancer predisposition syndrome Hereditary Non-Polyposis Colorectal Cancer (HNPCC). We continue to study the biophysical and genetic processes associated with our collection of over 50 human DNA repair genes and proteins as well as their connection with cancer, aging and fertility.

¹Several states, including Ohio have legislated that “Intelligent Design” - suggesting a “divine plan” is responsible for the existence and breadth of life on earth - be taught as a scientific alternative to Evolution “theory” in public schools. While it is true that Evolution is a theory (or more correctly a hypothesis) its validity and acceptance by the educated scientific community for over 100 years depends on sustained volumes of experimental tests, across such diverse disciplines as physics and chemistry. In contrast, there are no known experimental tests of “Intelligent Design”; thus placing it squarely in the category of a philosophy or a theology. Requiring “Intelligent Design” to be taught in a classroom of science remains the most visible political misconception of the scientific method, scholarly inquiry, and the prevarication of religious faith.