In addition to a local response, the phosphorylated CHK1s generated by a given lesion also contribute to a call for a global, cell-wide response--that response being cell cycle arrest  at the intra-S-phase checkpoint. But phosphorylated CHK1s generated by one or a small number of lesions won't be enough to initiate such a response. Cell cycle arrest can only be initiated by a quantity of phosphorylated CHK1 in the nucleus that can only be reached if there are many lesions or

Fork reversal If a DNA lesion isn't addressed by TLS or repriming in the first 20-30 minutes following RPA-ssDNA detection, fork reversal  will begin to unfold. In  this process, cell proteins rearrange the replication fork into a shape that makes the problematic lesion easier to repair. More precisely, the lesion is removed from the crowded active replisome environment with its clamps, polymerases, etc. and returns it back to the context of dsDNA, where it will be much easie

In the last post, we talked about fork protection , a posture that replication forks take when a lesion stalls a polymerase. Fork protection unfolds in minutes to tens of minutes after the cell detects RPA-dsDNA. Recall that it stabilizes the replisome structure and protects exposed DNA, giving the cell time to deal with the lesion. But fork protection is only the first part of a two-part process called fork stabilization . Fork stabilization also includes fork reversal. How

In the last post, I introduced the cell's two main DNA lesion repair pathways-- base excision repair (BER) and nucleotide excision repair (NER) . Both operate well beyond the replication fork during all of the phases of the cell cycle. But what happens if a lesion escapes BER and NER and finds itself in S phase in front of a moving replication fork? Most DNA lesions get past the CMG helicase but not the DNA polymerase, although some very large lesions can't get past the heli