We have examined the activity of different compounds on the frequency of single replication forks stalled at a strong block. Some recent results are summarized here: We have found that inhibitors of poly ADP ribose synthesis, which are used in cancer therapy, increase the frequency of single fork stalling. In contrast, inhibition of the degradation of poly ADP ribose reduces the frequency of single stalled forks. Resveratrol, which has received considerable attention as an anti-aging compound, had no effect on the replication patterns. A compound that enhances the activity of a protein chaperone that improves correct protein folding also reduces the frequency of single fork stalling events. Although it is very early in this project, our results suggest that some small molecule effectors can influence events at the level of the genome, such that the frequency of a genome destabilizing and stress inducing event is reduced. We plan to test additional compounds, and will follow those that show activity in the assay. We will also address the important question of how the compounds influence the replication patterns. The reduction in fork stalling could be due to increased efficiency of resolving the block, or a more effective response when the replication machinery encounters an impediment.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Investigator-Initiated Intramural Research Projects (ZIA)
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Trakselis, Michael A; Seidman, Michael M; Brosh Jr, Robert M (2017) Mechanistic insights into how CMG helicase facilitates replication past DNA roadblocks. DNA Repair (Amst) 55:76-82
Brosh Jr, Robert M; Bellani, Marina; Liu, Yie et al. (2017) Fanconi Anemia: A DNA repair disorder characterized by accelerated decline of the hematopoietic stem cell compartment and other features of aging. Ageing Res Rev 33:67-75