DNA damage-induced cell cycle checkpoints and DNA strand break repair in development and tumorigenesis

Several newly identified tumor suppressor genes including ATM, NBS1, BRCA1 and BRCA2 are involved in DNA double-strand break repair (DSBR) and DNA dam age-induced:checkpoint activation. Many of the gene products involved in ch eckpoint control and DSBR have been studied-in great detail in yeast. In ad dition to evolutionarily conserved proteins such as Chk1 and Chk2, studies in mammalian cells have identified novel proteins such as p53 in executing checkpoint control. DSBR:proteins including Mre11, Rad50, Rad51, Rad54, and Ku are present in yeast and in mammals. Many of the tumor suppressor gene products interact with these repair proteins as well as checkpoint regulato rs, thus providing a biochemical explanation for the pleiotropic phenotypes of mutant cells. This review focuses on the proteins mediating G1/S, S, an d G2/M checkpoint control in mammalian cells. In addition, mammalian DSBR p roteins and their activities are discussed. An intricate network among DNA damage signal transducers, cell cycle regulators and the DSBR pathways is i llustrated. Mouse knockout models for genes involved in these processes hav e provided valuable insights into their function, establishing genomic inst ability as a major contributing factor in tumorigenesis.