Visualizing the structure and coordination of the DNA replication machinery

2019

Challenge

A cell’s DNA must be faithfully copied every time it divides. The majority of miscarriages and cancers, as well as most mutations that cause human diseases, are caused by errors in DNA replication. To better understand how these conditions occur, scientists must uncover the molecular details of how DNA is copied, how the process can go wrong, and how to correct it.

Advance

A team of researchers led by IRP distinguished investigator Wei Yang, Ph.D., used cryo-electron microscopy to visualize the first-ever structure of a replisome, the set of proteins that organisms use to copy their DNA. Using a bacteria-infecting virus called a bacteriophage as their model system, the IRP scientists discovered that the enzyme that copies DNA, called DNA polymerase, plays a direct role in separating the two strands of the double-stranded DNA molecule. During DNA replication, DNA polymerase pulls on one strand of the DNA molecule while another enzyme, called helicase, pulls on the other strand, thereby unwinding the molecule and allowing it to be copied.

Impact

Although humans and bacteriophages represent dramatically different life forms and their DNA copying machines have evolved separately and independently for almost as long as life has existed on earth, the IRP team’s findings show that the basic architecture of the replisome and the cooperation of DNA polymerase and helicase are shared between humans and bacteriophages. As a result, understanding DNA replication in bacteriophages generates new insight into how the process occurs in human cells. More specifically, elucidating the way DNA polymerase and helicase work together to facilitate DNA replication provides critical insight into how replisomes are able to copy DNA so efficiently and how the two enzymes’ careful coordination can break down and lead to disease.

Publications

Gao Y, Cui Y, Fox T, Lin S, Wang H, de Val N, Zhou ZH, Yang W. (2019). Structures and operating principles of the replisome. Science. Feb 22;363(6429).