Bacteria help discover human cancer-causing proteins — ScienceDaily

"Our cells make protein carcinogens," mentioned co-corresponding writer Dr. Susan M. Rosenberg, Ben F. Love Chair in Cancer Research and professor of molecular and human genetics, of molecular virology and microbiology and of biochemistry and molecular biology at Baylor. "Cancer is a disease of mutations. A normal cell that has accumulated several mutations in particular genes becomes likely to turn into a cancer cell."

Mutations that trigger most cancers could be the results of DNA injury. External elements akin to tobacco smoke and daylight can injury DNA, however most DNA injury appears to consequence from occasions that happen inside cells and is mediated by mobile elements, together with proteins. Despite the significance of those occasions, they haven't been studied extensively.

"One way proteins can cause DNA damage is by being overproduced, which is a relatively frequent cellular event," mentioned Rosenberg, who is also chief of the Cancer Evolvability Program on the Dan L Duncan Comprehensive Cancer Center at Baylor. "In this study, we set out to uncover proteins that, when overproduced by the cell, cause damage to DNA in ways that can lead to cancer."

To uncover these DNA "damage-up" proteins, the researchers took an unconventional method. They looked for proteins that promote DNA injury in human cells by proteins that, when overproduced, would trigger DNA injury within the bacterium E. coli.

"Although bacteria and people are different, their basic biological processes are similar, so with this approach we thought we might find common mechanisms of DNA damage that could be relevant to cancer," Rosenberg mentioned.

"This was a wild idea," mentioned Rosenberg, and was attainable due to funding from two sources aimed toward making an attempt high-risk methods that, if profitable, would have excessive impression: a National Institutes of Health Director's Pioneer Award and a present from the W.M. Keck Foundation, amongst many different grants to the 16-lab crew.

E. coli reveals novel candidates for cancer-promoting proteins

The researchers genetically modified micro organism so they'd fluoresce pink when DNA was broken. Then, they overexpressed every of the four,000 genes current in E coli individually and decided which of them made micro organism glow pink.

"We uncovered an extensive and varied network of proteins that, when overproduced, alter cells in ways that lead to DNA damage," Rosenberg mentioned. "Some of these proteins are, as expected, involved in DNA processing or repair, but, surprisingly, most are not directly connected to DNA. For instance, some of the DNA damage-up proteins participate in the transport of molecules across the cell membrane."

When the researchers seemed for human protein kinfolk of the DNA "damage-up" proteins they'd present in micro organism, they recognized 284. Interestingly, they decided that these human proteins are linked to most cancers extra typically than random units of proteins. In addition, the proteins' RNAs, an indicator of protein manufacturing, predicted mutagenesis in tumors and poor affected person prognosis. When the researchers overproduced these proteins in human cells within the lab, half of the proteins triggered DNA injury and mutation.

"We confirmed that E. coli can help to determine DNA damage-up proteins and mechanisms of motion in human cells rapidly and inexpensively. Some of the proteins and their mechanisms had been recognized to be concerned in most cancers, however many others weren't suspected of being within the cancer-causing listing," mentioned co-corresponding writer Dr. Christophe Herman, professor of molecular and human genetics and molecular virology and microbiology at Baylor College of Medicine and member of the Dan L Duncan Comprehensive Cancer Center.

"I think it is extraordinary to identify so many ways DNA can be damaged. This study is opening up new avenues for discoveries of novel mechanisms that protect our genomes and how their dysfunction can alter the integrity of our DNA and cause cancer," mentioned co-corresponding writer Dr. Kyle M. Miller, affiliate professor of molecular biosciences on the University of Texas at Austin and member of the Dan L Duncan Comprehensive Cancer Center at Baylor. "It is yet another example of the power of model organisms to uncover basic biological processes that can shine a light on how human cells and cancer work."

"Our work has significant implications both in basic biological fields and in clinical research," Rosenberg mentioned. "We provide a previously unknown understanding of the diverse mechanisms that can generate DNA damage leading to cancer. In the future, this finding may lead to new ways to identify people who are likely to develop cancer so that strategies to prevent it, slow it down or catch it early can be used."

The examine's two co-first authors had been college students incomes their doctorates: Dr. Jun Xia at Baylor College of Medicine and Dr. Liya Chiu on the University of Texas at Austin.

For a whole listing of all of the contributors and their affiliations and the monetary help of this examine, go to the journal Cell.