PML nuclear body ; Fanconi anemia; interstrand DNA crosslink ; CHK1 inhibitors
Abstract
Abstract: Promyelocytic leukemia (PML) protein is the core component of subnuclear structures
called PML nuclear bodies that are known to play important roles in cell survival, DNA damage
responses, and DNA repair. Fanconi anemia (FA) proteins are required for repairing interstrand DNA
crosslinks (ICLs). Here we report a novel role of PML proteins, regulating the ICL repair pathway. We
found that depletion of the PML protein led to the significant reduction of damage-induced FANCD2
mono-ubiquitination and FANCD2 foci formation. Consistently, the cells treated with siRNA against
PML showed enhanced sensitivity to a crosslinking agent, mitomycin C. Further studies showed
that depletion of PML reduced the protein expression of FANCA, FANCG, and FANCD2 via reduced
transcriptional activity. Interestingly, we observed that damage-induced CHK1 phosphorylation was
severely impaired in cells with depleted PML, and we demonstrated that CHK1 regulates FANCA,
FANCG, and FANCD2 transcription. Finally, we showed that inhibition of CHK1 phosphorylation
further sensitized cancer cells to mitomycin C. Taken together, these findings suggest that the PML is
critical for damage-induced CHK1 phosphorylation, which is important for FA gene expression and
for repairing ICLs