The mre11 complex and the response to dysfunctional telomeres.

In this study, we examine the telomeric functions of the mammalian Mre11 complex by using hypomorphic Mre11 and Nbs1 mutants (Mre11(ATLD1/ATLD1) and Nbs1(Delta)(B/)(DeltaB), respectively). No telomere shortening was observed in Mre11(ATLD1/ATLD1) cells after extensive passage through culture, and the rate of telomere shortening in telomerase-deficient (Tert(Delta)(/)(Delta)) Mre11(ATLD1/ATLD1) cells was the same as that in Tert(Delta)(/)(Delta) alone. Although telomeres from late-passage Mre11(ATLD1/ATLD1) Tert(Delta)(/)(Delta) cells were as short as those from Tert(Delta)(/)(Delta), the incidence of telomere fusions was reduced.

Modeling disease in the mouse: lessons from DNA damage response and cell cycle control genes.

The advent of gene targeting has allowed the dissection of many essential cellular pathways, including those involved in cell cycle regulation, signal transduction, and development. However, it is becoming increasingly clear that the simple gene deletion strategy may not be sufficient for the modeling of many cancer syndromes. In this Prospect article, we will discuss the strengths and weaknesses of mouse models, how they have advanced from gene deletions to truncations, point mutations, and conditional mouse models in which expression or loss of the gene of interest is controlled either temporally or spatially.

Identification of a rare polymorphism in the human TP53 promoter.

The majority of families with classic Li-Fraumeni Syndrome (LFS) and a significant proportion of Li-Fraumeni-like (LFL) families have a germline mutation in the TP53 tumor suppressor gene. However around 20% of LFS and 60% of LFL families have no identifiable genetic defect in the coding region or splice junctions of TP53, and the genetic basis for cancer susceptibility in these families remains largely uncharacterized. To determine whether promoter mutations could be responsible for the Li-Fraumeni phenotype, we sequenced the TP53 promoter in index cases from members of classic LFS and LFL families without detectable TP53 mutations.