In Vivo Mouse Models of Double-strand Break Repair and Recombination

ABSTRACT Chromosomal double-strand breaks (DSBs) are formed during normal metabolic processes, following exposure to DNA damaging agents including irradiation, alkylating agents, and topoisomerase II poisons. DSBs are also implicated as forming as a result of exposure to a growing list of dietary compounds, supplements including bioflavonoids, and environmental toxins. DSBs are highly recombinogenic, increasing the exchange of information between two homologous DNA duplexes by several orders of magnitude, and cultured mammalian cells do utilize this mechanism to faithfully restore sequence following DSBs. Although the role of HR is well appreciated in meiosis of prokaryotes, yeast, and metazoans, the role of interchromosomal HR to occur in vivo in somatic cells of mammals is only minimally understood although it has the potential to promote genome stability, and also genetic diversity, chromosomal rearrangements, and drive evolution. Our laboratory established unique mouse models to determine the potential of DSBs to promote DSB induced recombination in vivo. These models were the first to demonstrate that interchromosomal HR occurs in vivo in multiple organ systems, and provide an ideal platform to further elucidate which cells at specific developmental stages of development or differentiation may be most likely to undergo this type of DSB repair. Further we will determine if altered altered expression of one protein central to DSB repair and recombination?Rad51--is sufficient to promote promiscuous interchromosomal HR. This work will lead to an understanding of the fundamental mechanisms of DSB rejoining at the chromosomal level, and also provide insight on genome stability and genetic evolution. Further, there is a growing list of dietary supplements and environmental toxins that promote or stabilize chromosomal DSBs, and thus our findings may have implications to the susceptibility of differentiating somatic cell types to mutagenic DSB repair and genome rearrangements that may result from exposure to them.