This is consistent with a transient checkpoint-mediated cell-cycle arrest followed by recovery of proliferative capacity.
Taken together, these data suggest that transient checkpoint responses may represent a hitherto unappreciated mechanism that allows TICs to evade DNA damage-induced apoptosis.
There is increasing evidence that activation of P38 MAPK by stress stimuli may not necessarily promote cell death but instead also enhance cell survival through activation of a transient G2/M cell cycle checkpoint and successful DNA damage repair.
Unlike doxorubicin, which causes double-stranded DNA breaks and chronic G2 arrest accompanied by 'templated' CA, Red-Br-nos-mediated DNA damage elicits de novo CA during a transient S/G2 stall, followed by checkpoint abrogation and mitotic entry to form aberrant mitotic figures with supernumerary spindle poles.
In budding yeast, we show involvement of Spc105p/Kre28p in checkpoint activity as we observed reduced levels of the Mad2 and Bub1 checkpoint proteins on unattached kinetochores in spc105 mutants, resulting in a transient but not a normally sustained checkpoint-mediated delay in the face of MT depolymerization.
The core of the timer model lies in that checkpoint recovery can be committed spontaneously after prolonged checkpoint arrest with or without completion of DNA repair, which notion was possibly reflected in previous studies that revealed a transient nature of the G2/M damage checkpoint [ 60, 61].
Nbs1, the SMC1 component of cohesin, and activating transcription factor 2 (ATF2) have been identified as critical ATM targets in the intra-S checkpoint response, 12, 25 and cells in S-phase exposed to DNA damage activate the intra-S phase checkpoint, leading to a transient reduction in DNA synthesis.
Checkpoint-proficient cells undergo a transient delay in mitotic entry upon exposure to damage [7].
The recovery of mitotic cells 6 and 12 hr post-IR and the decline in G2 cells 6 24 hr post-IR indicate that the G2 checkpoint response to IR was a transient arrest that was largely reversed by 6 hr.
However, a transient arrest of cells, due to activation of the mitotic spindle checkpoint, cannot be excluded completely.
