DNA repair and recombination and their roles in genome stability and tumor suppression

My lab's research interest is the repair of DNA damage via homologous recombination (homologous recombinational repair; HRR). and the critical roles this pathway plays in genomic stability and tumor suppression. That deficient DNA repair can predispose to tumorogenesis is well established in relation to other major DNA repair pathways. Defects in nucleotide excision repair underlie xeroderma pigmentosum. which confers extreme risk of skin cancer. Defects in mismatch repair cause hereditary non-polyposis colon cancer. The principle evidently extends to defects in HRR. which are strongly correlated with genomic instability at levels ranging from localized sequence rearrangement to gross chromosomal change.

This correlation is illustrated by the HRR gene XRCC3. Cells mutated for XRCC3 are hypersensitive to certain types of DNA damage and show extreme chromosomal instability. with high frequencies of chromosome breakage. rearrangements and loss [publication #8. below]. They are severely impaired for HRR of chromosomal breaks. showing not only reduced overall efficiency of repair [7]. but also a loss of fidelity such that rearrangements of chromosomal DNA often accompany repair [4]. Similar phenotypes of chromosomal instability and hypersensitivity to DNA damage have been seen for a growing list of genes with known or suspected involvement in HRR. These include other members of the RAD51 gene family (to which XRCC3 belongs). and genes linked to several cancer predisposition syndromes. including Nijmegen Breakage Syndrome (NBS1). Bloom Syndrome (BLM). Werner Syndrome (WRN). and familial breast cancer (BRCA1 and BRCA2).

Defective HRR has now been causally linked to tumorogenesis through BRCA1 and BRCA2; the first tumor suppressor genes shown unequivocally to function in HRR [reviewed in 6]. In mouse. complete gene knockout of BRCA2 is lethal. A milder mutation permits viability. but results in hypersensitivity to DNA crosslinking damage and frequent breakage or loss of chromosomes [3]. In human cells. disrupting functional interaction between the BRCA2 and RAD51 proteins also causes DNA damage hypersensitivity. and impaired HRR of chromosomal breaks [1]. Still unknown is why breast tissue should be especially susceptible to this defect. and whether loss of BRCA2 function represents a "weak link" in a chain of tumorogenic events common to non-familial ("sporadic") breast cancer as well. Answers to these questions may help us understand and combat the alarming increases in incidence of breast cancer seen over the past few decades.

New research directions include investigations of the molecular mechanisms by which BRCA2 and the RAD51 family proteins function in HRR. A particularly important aspect is the repair and/or bypass of DNA damage encountered by replication forks. and how mutations that impair this process. or environmental exposures that overwhelm it. might drive genomic instability and tumorogenesis. These studies will be extended to other tumor suppressor proteins (BRCA1. NBS1. BLM. and WRN). A parallel interest is exploiting new knowledge about HRR to develop techniques for high-efficiency gene targeting in human cells. This would enable the kind of fascile genetic analysis that is currently possible only in bacteria and yeast. and holds great promise for therapeutic intervention in genetic disease.

View Dr. Brenneman's publications in Pub Med