Figure 2.

Mechanisms proposed for spontaneous telomere loss in cancer cells. During DNA replication, the two DNA strands (blue lines) are converted into four strands as the replication fork progresses. Telomere loss in cancer cells occurs because replication forks stall at fragile sites, which includes telomeres, as a result of replication stress caused by continuous cell division. The failure to stabilize stalled replication forks in the proximity of a telomere would result in replication fork collapse and the formation of a double-strand break (DSBs), causing the loss of the terminal fragment containing the telomere. Similarly, replication forks encountering an I-SceI-induced DSB near a telomere would also result in telomere loss. Alternatively, the increased frequency of loss of the terminal fragment containing the telomere could result from a deficiency in DSB repair near telomeres. Finally, a failure to stabilize the chromosome after the loss of the telomere due to a deficiency in chromosome healing in cancer cells would further increase the likelihood of sister chromatid fusion or other gross chromosome rearrangements, which would then initiate chromosome instability.