Rosenberg and colleagues carried out this study in the laboratory bacterium E. coli, which they and others have shown to be a reliable model of the genetic changes that occur in animal cells. In their paper, they discovered a new role of an E. coli protein related to five human cancer proteins. They then analyzed gene expression data from human cancers and were able to implicate two of the five E. coli-related human cancer proteins in potentially promoting cancer by a similar mechanism – one not previously implicated.
“The most exciting part in this paper for me is that we can learn something new about the mechanisms of cancer from the E. coli model,” said co-first author Qian Mei, who is a research assistant in the Rosenberg lab and a graduate student in the Systems, Synthetic and Physical Biology (SSPB) program at Rice University. “Even though bacteria and human cells are very different, many DNA repair proteins are highly conserved through evolution; this makes E. coli a good model to study how cells repair DNA or accumulate mutations.”
Rosenberg and colleagues think that their approach offers significant advantages. For instance, with the synthetic proteins, they have been able to identify specific DNA-repair intermediate molecules, their numbers in cells, rates of formation and locations in the genome and the molecular reactions in which they participate.
“It is most exciting that we are now able to trap, map and quantify transient DNA reaction intermediates in single living cells,” said co-first author Jun Xia, graduate student in the Rosenberg lab and in the Integrative Molecular and Biomedical Sciences program at Baylor. “This new technology helps us reveal the origins of genome instability.”
“When you know these reactions and the role each intermediate plays in the mechanisms that change DNA, you can think about making drugs that will stop them,” said Rosenberg. “In the future we hope we will be able to design drugs that target specific types of cancers; drugs that block the cells’ ability to evolve into cancer cells, instead of, or in addition to, traditional chemotherapies that kill or stop cancer cells from growing.”
Other contributors to this work include Li-Tzu Chen, Chien-Hui Ma, Jennifer A. Halliday, Hsin-Yu Lin, David Magnan, John P. Pribis, Devon M. Fitzgerald, Holly M. Hamilton, Megan Richters, Ralf B. Nehring, Xi Shen, Lei Li, David Bates, P.J. Hastings, Christophe Herman and Makkuni Jayaram.
This work was supported by a gift from the WM Keck Foundation, and its early stages were supported by a National Institutes of Health Director’s Pioneer Award DP1-CA174424 to Rosenberg. The work also was supported by the National Aeronautics and Space Administration through the NASA Astrobiology Institute under Cooperative Agreement No. NNA13AA91A issued though the Science Mission Directorate, Cancer Prevention and Research Institute of Texas (CPRIT) RP140553, and CPRIT Baylor College of Medicine Comprehensive Cancer Training Program Postdoctoral Fellowship RP160283, NIH R01 grants CA190635, GM102679, GM106373, GM88653, National Science Foundation grant MCB1049925, Robert F Welch Foundation Award F-1274, and the Baylor College of Medicine (BCM) Cytometry and Cell Sorting Core with funding from the NIH (P30-AI036211, P30-CA125123, and S10-RR024574), and the BCM Integrated Microscopy Core with funding from the NIH (HD007495, DK56338, and CA125123) and CPRIT RP150578, the Dan L Duncan Comprehensive Cancer Center and the John S. Dunn Gulf Coast Consortium for Chemical Genomics.