Selectively killing transformed cells through proteasome inhibition

consistent with origin activation during the 1st pulse period; (2) Uni-directional forks—contain a track of 1st label with an adjacent track of 2nd label, consistent with individual growing forks; (3) Clustered replicons—contain intermingled and contiguous tracks of 1st and 2nd label, which must represent clustered replicons that engaged and completed synthesis during labelling. Because labelling was performed for 30 min, origins in clustered replicons must be <50kbp apart; (4) Terminated forks—contain a track of 2nd label with two flanking tracks of the 1st, consistent with opposing forks that meet during the 2nd pulse period. Fiber analysis was performed at 1 h intervals during transit through S phase. As expected, replication at the onset of S phase correlated with a high frequency of bi-direction forks from origins that were activated during labelling; most of the remainder were growing forks. Interestingly, in the following period of synthesis—between 1st and 2nd h of S phase—origin activation in normal cells fell to the level seen throughout the remainder of S phase whereas Notably, fiber analysis has shown that checkpoint proteins contribute to the suppression or squelching of redundant potential origins9 and regulate the transition from early to mid/ late S phase.10