title: DNA repair pathways and hereditary cancer susceptibility syndromes.
abstract: Every living organism is exposed to numerous genomic insults on a daily basis as a consequence of cellular metabolism and exposure to environmental agents capable of interacting with the genome (e.g. chemicals, toxins, pollutants, UV and ionizing radiation) (1). Maintenance of the integrity of the genome is paramount to the survival and propagation of a species and involves the continuous activity of a variety of DNA repair pathways. Inherited mutations in genes involved in DNA damage recognition and repair lead to disease by destabilization of the genome and increased mutagenesis. In fact, it is common for cancer cells to exhibit loss of genomic stability presumably as a result of clonally acquired mutations in DNA repair genes (2). Currently, roughly 150 DNA repair genes have been identified in humans (3) and a variety of familial cancer predisposition and/or premature aging syndromes are now linked to various loss-of-function mutations in these genes (4). Genetic interaction between DNA repair pathways and global cell differentiation pathways is supported by phenotypic similarities between inactivating mutations in a DNA repair, cell cycle arrest and apoptosis proteins. Though there is clearly some degree of functional redundancy between DNA repair pathways for correction of specific DNA lesions, the particular clinical characteristics of a repair defect can be predicted by the specific repair pathway affected (5). Patients with cancer predisposition syndromes often have multiple family members affected by cancer, develop cancer at an early age, and are at risk for developing multiple primary tumors over time (6, 7). Though patients with identifiable cancer predisposition syndromes are rare, defining their molecular defects has led to widespread applicability by uncovering relevant molecular pathways that are perturbed via somatic (non-inherited) mutations in the majority of sporadic cancers. In this review, we describe general molecular mechanisms of major forms of DNA repair and illustrate clinical consequences of deficiencies in these pathways. For more in depth detail, the reader is referred to several recent reviews and texts (2, 8-13).
authors.affiliation: The Graduate Center for Toxicology, University of Kentucky College of Medicine, Lexington, KY 40536-0096, USA.
authors.forename: Malinda
authors.initials: M
authors.lastname: Spry
authors.forename: Tim
authors.initials: T
authors.lastname: Scott
authors.forename: Heather
authors.initials: H
authors.lastname: Pierce
authors.forename: John A
authors.initials: JA
authors.lastname: D'Orazio
mesh_terms: D004260:DNA Repair; D020022:Genetic Predisposition to Disease; D006801:Humans; D009369:Neoplasms / Q000235:genetics*