ATM-DEPENDENT INTERACTIONS OF A MAMMALIAN CHK1 HOMOLOG WITH MEIOTIC CHROMOSOMES

Background: Checkpoint pathways prevent cell-cycle progression in the event of DNA lesions, Checkpoints are well defined in mitosis, where l esions can be the result of extrinsic damage, and they are critical in meiosis, where DNA breaks are a programmed step in meiotic recombinat ion. In mitotic yeast cells, the Chk1 protein couples DNA repair to th e cell-cycle machinery. The Atm and Atr proteins are mitotic cell-cycl e proteins that also associate with chromatin during meiotic prophase 1. The genetic and regulatory interaction between Arm and mammalian Ch k1 appears to be important for integrating DNA-damage repair with cell -cycle arrest. Results: We have identified structural homologs of yeas t Chk1 in human and mouse. Chk1(Hu/Mo) has protein kinase activity and is expressed in the testis. Chk1 accumulates in late zygotene and pac hytene spermatocytes and is present along synapsed meiotic chromosomes , Chk1 localizes along the unsynapsed axes of X and Y chromosomes in p achytene spermatocytes. The association of Chk1 with meiotic chromosom es and levels of Chk1 protein depend upon a functional Atm gene produc t, but Chk1 is not dependent upon p53 for meiosis I functions, Mapping of CHK1 to human chromosomes indicates that the gene is located at 11 q22-23, a region marked by frequent deletions and loss of heterozygosi ty in human tumors. Conclusions: The Atm-dependent presence of Chk1 in mouse cells and along meiotic chromosomes, and the late pachynema co- localization of Atr and Chk1 on the unsynapsed axes of the paired X an d Y chromosomes, suggest that Chk1 acts as an integrator for Atm and A tr signals and may be involved in monitoring the processing of meiotic recombination. Furthermore, mapping of the CHK1 gene to a region of f requent loss of heterozygosity in human tumors at 11q22-23 indicates t hat the CHK1 gene is a candidate tumor suppressor gene.