Protein averts cell suicide but might contribute to cancer

But they also discovered that this protein, an enzyme called Dpo4, often makes errors when copying the genomic DNA sequence that later might cause the cell to become cancerous.

The findings by researchers with Ohio State University 's Comprehensive Cancer Center are described in two back-to-back papers in The Journal of Biological Chemistry.

"Unrepaired DNA damage presents a big roadblock for the DNA replication machinery, which cannot go around it," says Zucai Suo, assistant professor of biochemistry. "This damage will trigger cell death because the DNA is not replicated.

"This protein bypasses the damage and saves cells from self-destructing, but it is very error prone, which suggests that it may also play a role in cancer."

Dpo4 is one of a family of enzymes called Y-family DNA polymerases that were first discovered about 10 years ago and are only now becoming understood.

"These enzymes provide a survival mechanism for cells," says first author Kevin Fiala, a graduate student in Suo's laboratory. "They allow DNA replication to continue, so the cell doesn't die. But they don't repair the DNA damage that exists."

DNA damage is a routine problem for cells, Suo says. For example, every cell loses more than 10,000 DNA bases daily. Dedicated repair enzymes fix 80 percent or more of this damage, but the rest remains.

Cells use Y-family enzymes to bypass that remaining damage when making new DNA prior to cell division, thus forcing these enzymes to copy damaged DNA.

How these bypass enzymes work, however, isn't known. The Dpo4 protein used in this research comes from a microorganism. It is relatively easy to produce in large quantities and to study, and it is similar to one of the four such enzymes found in humans.

For this research, Fiala developed a new way to sequence very short lengths of DNA. "This allowed us to pin down exactly what mistakes Dpo4 makes," he says.

The findings reveal why the enzyme makes mistakes.

DNA resembles a spiral staircase that is made from separate halves, with half-steps protruding from each. The half-steps fit together down the center to form the complete staircase.

In DNA, the half-steps are known as the bases – the ‘A's, ‘C's, ‘G's and ‘T's – that run the length of a DNA helix. A complete step is formed by pairs of bases according to a rule: ‘A' always pairs with ‘T,' and ‘C' always pairs with ‘G.'

When cells make new DNA, the two strands separate, and each old half becomes a template for a new partner. The DNA-making machinery travels along the old half, building the new half according to the bases it finds on the old half. When it meets an ‘A' on the old half, it pairs it with a ‘T' on the new half (and vice versa); when it meets a ‘G' on the old half, it pairs it with a ‘C' on the new strand. In the end, there are two complete DNA molecules instead of one, each made up of an old half and a new half.

But trouble arises during the building if one of the bases – one of the half steps – is missing. When the DNA replication machine encounters the gap, it stalls. If the standstill continues, the cell will self-destruct.

It's at this point when Dpo4 jumps in. It adds a base opposite the gap and then leaves, allowing the DNA-making machinery to bypass the damage and continue construction.

The action averts cell suicide, but the gap – and the stop-gap base – might become a mutation that, in conjunction with later genetic damage, causes the cell to eventually become cancerous.

"The objective of this enzyme is to allow replication to continue, not to repair the damage," says Fiala. The damage will persist, and cells might try to repair it later. But as long as DNA replication can continue, the cell survives."

Currently, Suo's laboratory is investigating human Y-family DNA polymerases.

Source: Ohio State University

Brainy genes, not brawn, key to success on mussel beach
It's hard being a mussel: you have to worry about hungry starfish and even hungrier humans, not to mention an environment that can change your body temperature 50 degrees Fahrenheit in just a few hours.
Form of Crohn's disease traced to disabled gut cells
Scientists report online this week in Nature that they have linked the health of specialized gut immune cells to a gene associated with Crohn's disease, an often debilitating and increasingly prevalent inflammatory bowel disorder.
First glimpse of a key DNA repair protein at work
Repairing breaks in the two strands of the DNA double helix is critical for avoiding cancer. In humans and other organisms, a molecular machine called the MRN complex is responsible for finding and signaling double-strand breaks (DSBs), then launching the error-free method of DNA repair called homologous recombination.
Researchers reveal Epstein-Barr virus protein contributes to cancer
Researchers at the University of Toronto have shown that the EBNA1 protein of Epstein-Barr virus (EBV) disrupts structures in the nucleus of nasopharyngeal carcinoma (NPC) cells, thereby interfering with cellular processes that normally prevent cancer development. The study, published October 3rd in the open-access journal PLoS Pathogens, describes a novel mechanism by which viral proteins contribute to carcinogenesis.
Biochemists devise method for bypassing aluminum toxicity effects in plants
(PhysOrg.com) -- Aluminum toxicity, a global agricultural problem, halts root growth in plants, severely limiting agricultural productivity for more than half of the world's arable land.
Cells that Avoid Suicide May Become Cancerous
(PhysOrg.com) -- When a cell's chromosomes lose their ends, the cell usually kills itself to stem the genetic damage. But University of Utah biologists discovered how those cells can evade suicide and start down the path to cancer.
Photonic crystal biosensors detect protein-DNA interactions
Scientists at the University of Illinois have developed a new class of disposable, microplate-based optical biosensors capable of detecting protein-DNA interactions. Based on the properties of photonic crystals, the biosensors are suitable for the rapid identification of inhibitors of protein-nucleic acid and protein-protein interactions.
Research indicates new virus is culprit, not bystander, in deadly skin cancer
University of Pittsburgh scientists are uncovering more evidence that a virus they recently discovered is the cause of Merkel cell carcinoma, an aggressive and deadly form of skin cancer.

Protein averts cell suicide but might contribute to cancer

Related stories:

News discussion: