Throughout a cell’s lifespan, the integrity of its DNA is challenged by exposure to genotoxic agents such as radiation or toxic chemicals in the environment. The cumulative DNA damage is thought to underlie the development of cancer and other genetic diseases.
Fortunately, our cells have evolved a DNA damage response, or DDR, to correct genetic damage before it is passed on to future generations. In actively dividing cells, halting the cell cycle is the first major consequence of DDR activation, allowing the repair process to take place before chromosomes are segregated into daughter cells.
To understand the role of key proteins in the DNA damage response, a team of researchers led by Uttam Surana, a Research Director at A*STAR’s Institute of Molecular and Cell Biology (IMCB), in collaboration with Hong Hwa Lim, a Principal Scientist at A*STAR’s Bioprocessing Technology Institute (BTI) and IMCB, decided to study Dun1, a protein known for its role in ‘switching on’ genes that repair damaged DNA.
“Earlier reports suggested that Dun1’s role in the DNA damage response is through the transcription regulation of repair genes. Our study shows that Dun1 plays another critical role in maintaining checkpoint arrest and preventing the segregation of damaged chromosomes into the daughter cells,” Surana said.
Dun1’s additional important role in the DNA damage response has to do with the role it plays in a surveillance mechanism called checkpoint control, which immediately ‘pauses’ or arrests the cell cycle to enable DNA repair before cell division can resume.
Surana and his team found that Dun1 arrests the cell cycle when DNA damage is detected by indirectly preventing the separation of duplicated chromosomes and their partitioning into the daughter cells. Dun 1 does this by inhibiting the activity of an ubiquitin ligase protein called Rsp5, thus preventing the degradation of securin and allowing it to continue to inhibit the separation of damaged chromosomes until they are repaired.
These findings were made in yeast, where the genes and proteins involved in regulating the cell cycle and checkpoint control were first discovered, and have since been found to be evolutionarily conserved in humans. The equivalent of securin in yeast, for example, is Pds1.
In the future, Surana wants to examine these DDR pathways in human cells and bridge these pathways with their role in cancer. “We hope to extend our findings to human cancer cells with deregulated cell cycle dynamics, where cells continue to proliferate despite the presence of genomic instability,” he said.
The A*STAR-affiliated researchers contributing to this research are from the Institute of Molecular and Cell Biology (IMCB), the Bioprocessing Technology Institute (BTI) and Biotransformation Innovation Platform.