Do we really know how DNA replicates?

A recent discovery shows that DNA replication is fundamentally different from our current understanding of the process.

WrittenBy:Science Desk
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By Sahana Shankar

DNA, the term, has taken a life of its own in the social parlance.  It is no longer restricted to scientific labs. Corporate houses use the phrase ‘integral part of the company’s DNA’ to emphasise their core values. Soap operas ruthlessly use DNA to solve crimes and disputed paternity, some cleverly and some with no connection to scientific accuracy. DNA has been an important tool to explain human evolution and migration. It tackles the racism debate by debunking myths of ‘pure’ ancestry.

The elegantly simple double-helix structure of DNA, decoded by Watson and Crick in 1953 unravelled a new era in genetics. It helped understand genes, mutations and the theory of inheritance. The ability to manipulate DNA has spawned the entire molecular biology world, where we can improve nutrition, quality of food crops, develop safer and more efficient drugs and better understand diseases like cancer and haemophilia.

In spite of all our efforts to understand DNA, it remains somewhat of an enigma. A recent fascinating discovery by scientists at the University of California, Davis has demonstrated that all we know about how the cell duplicates the DNA before dividing into two may be fundamentally different from what actually goes on.

It is now common knowledge that DNA is the blueprint of life, which is passed on to every daughter cell.  Before a cell undergoes division, it faithfully duplicates all of its DNA into another copy by a process called DNA replication. The DNA inside the cell exists in a supercoiled form and is unwound by an enzyme, helicase. Another enzyme, primase attaches a complementary primer to the opened strands. The two strands are then copied in two different ways by a third enzyme, DNA polymerase. One strand is copied continuously from end to end, while the other is copied in short stretches which are then stitched together. Thus, when the cell divides, each daughter cell gets one complete set of DNA in which one strand is the parental strand and the other is the newly synthesised strand. This semi-conservative method of DNA replication is conserved across all forms of life from bacteria to humans. The complexity of the enzyme machinery may vary from species to species. However, the fundamental mechanism remains the same.

The team of Dr Stephen Kowalczykowski, a professor of microbiology and molecular genetics at the UC Davis, devised a special microscope which could visualise replication of individual DNA molecules, extracted from bacteria E.coli, and measure the speeds of respective enzymes at work. The experimental set up included attaching a piece of circular DNA onto a slide with a short overhang. As the DNA is replicated, the overhang increases in length. The enzymes could be turned on and off by adding or removing Adenosine triphosphate (ATP), the energy molecule that drives the process. Using a fluorescent dye, the scientists could selectively identify DNA in double-stranded form.

By convention, the polymerases on the two strands were expected to process the DNA at the same speed. However, the study showed that the polymerases on the two strands moved at different speeds. Sometimes, replication on one of the strands would continue while synthesis on the other strand stopped or the two strands were copied at different speeds. This suggests that the two strands are not in coordination and DNA replication is likely a process of random starts, stops and differing speeds of the processing enzymes. Kowalczykowski explains it with a metaphor—traffic on a highway. “Sometimes the traffic in the next lane is moving faster and passing you, and then you pass it. But if you travel far enough you get to the same place at the same time.” Interestingly, the helicase seemed to have an internal brake where it would slow down when the two strands are copied at different speeds to prevent damaging single-stranded DNA, which can be attacked by other enzymes.

DNA replication is a tightly regulated process and the enzymes involved are high-fidelity polymerases which do not allow any mismatches between the parental and daughter strand. The different processivity (an enzyme’s ability to catalyse consecutive reactions) of the polymerase on the two parental strands is a paradigm shift in the field. We need to understand how DNA is faithfully copied, in spite of a seemingly stochastic replication process. Since DNA replication is an attractive target for cancer therapy, a thorough understanding of the process can help develop efficient anti-tumor drugs. With further work, this breakthrough would require textbooks to be rewritten.


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