ABSTRACT
A subset of human cancer syndromes result from inherited defects in genes responsible for DNA repair. During the past few years, discoveries concerning the intersection of certain DNA repair processes have increased our understanding of how the disruption of specific DNA repair mechanisms leads to genomic instability and tumorigenesis. This review focuses on the human genes MUTYH, BRCA2/FANCD1, and BLM.
Subject(s)
DNA Repair/genetics , Neoplastic Syndromes, Hereditary/genetics , Adenosine Triphosphatases/genetics , Adenosine Triphosphatases/metabolism , BRCA2 Protein/genetics , BRCA2 Protein/metabolism , Bloom Syndrome/genetics , Bloom Syndrome/metabolism , Colorectal Neoplasms/genetics , DNA Glycosylases/genetics , DNA Glycosylases/metabolism , DNA Helicases/genetics , DNA Helicases/metabolism , Fanconi Anemia/genetics , Fanconi Anemia/metabolism , Humans , Models, Genetic , Mutation , Neoplastic Syndromes, Hereditary/metabolism , RecQ HelicasesABSTRACT
Persons with the autosomal recessive disorder Bloom syndrome are predisposed to cancers of many types due to loss-of-function mutations in the BLM gene, which encodes a recQ-like helicase. Here we show that mice heterozygous for a targeted null mutation of Blm, the murine homolog of BLM, develop lymphoma earlier than wild-type littermates in response to challenge with murine leukemia virus and develop twice the number of intestinal tumors when crossed with mice carrying a mutation in the Apc tumor suppressor. These observations indicate that Blm is a modifier of tumor formation in the mouse and that Blm haploinsufficiency is associated with tumor predisposition, a finding with important implications for cancer risk in humans.
