How human cells coordinate the onset of DNA reproduction

IMAGE: The Origin Recognition Complex (ORC) is a group of proteins that must be fully assembled for the first step in DNA reproduction. One part of the ORC, ORC1 (shown in … view more

Credit: Manzar Hossain / Stillman lab / CSHL, 2021

Cold Spring Laboratory President (CSHL) Bruce Stillman has been breaking DNA replication, a critical step in cell division, since the 1980s. His laboratory examines how Origin Recognition Complexes – ORCs – coordinate DNA duplication. They found out how our cells accumulate and destroy ORCs during the cell division cycle. One ORC protein is trapped in tiny droplets, holding it away until the right time for other proteins to recruit and start DNA reproduction.

The ORC understands where reproduction should begin at several locations on the long, linear layers of DNA in the chromosomes of our cells. Fully assembled ORCs employ other proteins to produce exact copies of the chromosomes. This equipment is essential for proper DNA acquisition without errors that can cause disorders such as cancer.

Scientists have studied the structure of ORC in several species. Stillman explains:

“We’ve studied this before in baker’s yeast, but human cells seem to have a different way of doing things.”

Unlike single-cellar yeast, humans have several cells that divide at different times. To study this, the researchers found that one human ORC protein, ORC1, has specific components that are yeast ORC1. When ORC binds to DNA, ORC1 employs CDC6, a protein that accumulates other DNA replication proteins. Some specific human regions of ORC1 and CDC6 bind to other proteins that regulate DNA reproduction. Manzar Hossain, a research investigator at the Stillman Laboratory, says:

“We found that ORC1 and CDC6 interact in a very similar way. We found a very short time frame that allows them to interact.”

DNA-bound ORC1 is trapped in molten droplets that change shape, and then ingest CDC6. Kuhulika Bhalla, a postdoc in the Stillman lab, explains:

“So if you can think of a lava lamp, like you have a liquid, but it contains another colored liquid. And they still got separated.”

Throughout the cell division cycle, ORC1 and CDC6 open in the cell. Stillman explains that “both high and low levels of ORC1 lead to severe effects on cell viability. So you just need to have the right amount ”of each protein throughout the cell cycle. Stillman and his colleagues have shown that CDC6 employs other regulatory proteins that control ORC1 activity and levels both in space and in time. They published their findings in Cell molecular.

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