Karlene Cimprich, Ph.D.
A new NIEHS-funded study sheds light on how cells resolve DNA damage and maintain genomic stability during replication. Researchers identified the protein helicase-like transcription factor (HLTF) as a key regulator of the cellular replication stress response. The protein prevents genomic instability known to contribute to many diseases, such as cancer.
Using cells with and without HLTF, the researchers studied mechanisms and pathways by which cells overcome DNA replication stress, which can stall replication and cause genome instability. They used genetic and imaging approaches to identify which DNA damage tolerance pathways help replication progression.
The team found that in cells without HLTF, DNA replication did not slow down at the site of replication under stress. Instead, with increased resistance to replication stress, DNA replication continued unrestrained through other mechanisms. In this context, unrestrained replication can lead to a reduction in certain forms of DNA damage, possibly at the expense of reducing other such damage.
According to the authors, HLTF is important in regulating replication and preventing alternative mechanisms that can lead to potentially mutagenic forms of DNA replication related to tumor formation. Their findings also illustrate the adaptability of replication in responding to chemotherapy or other threats to genome integrity.
Citation: Bai G, Kermi C, Stoy H, Bacal J, Zaino AM, Hadden MK, Eichman BT, Lopes M, Cimprich KA. 2020. HLTF promotes fork reversal, limiting replication stress resistance and preventing multiple mechanisms of unrestrained DNA synthesis. Mol Cell 78(6):1237-1251.