Replication fork slowing and stalling are distinct, checkpoint-independent consequences of replicating damaged DNA

Dr. Nick Rhind and Dr. Divya Ramalingam Iyer published a paper in the PLOS Genetics Journal in August. In this paper, Dr. Rhind’s team has looked at how individual forks behave in response to DNA damage and how the intra-S checkpoint regulates their response. Regulation of forks in response to DNA damage is perhaps the most crucial role of the intra-S checkpoint however its mechanisms are not understood. To address these questions they have used DNA combing, a single-molecule technique that allows them to visualize individual forks. They find that forks pass most DNA damage-induced lesions with only a brief pause and that this lesion bypass is checkpoint independent. However, at a low frequency, forks stall at lesions, and that the checkpoint is required to prevent these stalls from accumulating excess single-stranded DNA. Their results suggest that the major role of the checkpoint is not to regulate the interaction of replication forks with DNA damage, per se, but to mitigate the consequences of fork stalling when forks are unable to successfully navigate DNA damage on their own.

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