DNA damage responses in the prostate

Abstract

Comment on: Zhewei Z, et al. Cell Cycle 2011; 10:3545-53.

Progress in understanding the origins of prostate cancer is hindered by a lack of relevant in vivo human models, but in a recent article, Zhang et al.1 demonstrate the utility of ex vivo culturing of slices of normal prostate tissue obtained from surgeries. The prostate is composed primarily of two cell types, basal and luminal cells, but prostate cancer is commonly believed to originate from the luminal cells because tumor biopsies exhibit luminal cell expansion coupled with an absence of basal cells.2 However, both cell lineages may harbor potential cancer cells.3,4

Zhang et al.1 report that the basal and luminal epithelial cells exhibit substantially different responses to DNA damage. In basal cells, phosphorylation of H2AX and KAP1 was found to be dependent on ATM and to follow kinetics considered typical of a robust DNA damage response, while these phosphorylations were attenuated in the luminal cells. On the other hand, DNA-PK was phosphorylated in both cell types, suggesting that DNA-PK-dependent repair was activated in the luminal cells despite the diminished H2AX and KAP1 responses.

Since these studies cannot reveal what specifically is occurring at the DNA level in response to DNA damaging agents, it is not known what qualitative or quantitative differences might exist in the repaired DNA in these two cell types. In previous work, the same laboratories presented evidence that the subdued H2AX response may be due to lower H2AX levels in the luminal cells.5 since H2AX is considered essential for the rapid phase of DNA DSB rejoining, but expendable for DSB rejoining itself,6 one might expect differences in the rates of DSB repair in these two cell types. Also, there is evidence that the presence of H2AX and γ-H2AX foci in a cell may make for more accurate DNA rejoining at DSBs,7 supporting the notion that DNA repair in luminal cells may be less accurate than in basal cells.

On the other hand, in spite of exhibiting radiation hypersensitivity, defective class-switch recombination, and male sterility, the H2AX-null mouse has a normal physical phenotype, indicating that rapid DSB repair may not be essential for organisms living in unstressed circumstances. Cells taken from the H2AX-null mouse and induced to proliferate in culture exhibit multiple genome defects,5 but how the lack of H2AX affects genome stability in non- or slowly proliferating cells is still not clear.

In summary, the studies by Zhang et al.1 suggest that DNA damage in the prostate is processed by different pathways in different cell types under as close to in vivo conditions as can be currently obtained experimentally, and offer a plausible hypothesis for differential mutability of different cell types. Being able to elucidate and compare DNA repair in different cell and tissue types in normal human tissues will help enlighten the processes of oncogenesis in humans.