Tethering of Shattered Chromosomal Fragments Paves Way for New Cancer Therapies

“It’s similar to a smashed car windshield, where the safety glass is designed to keep all of the broken pieces in place,” said senior study author Don W. Cleveland, PhD, Distinguished Professor and chair of the Department of Cellular and Molecular Medicine at UC San Diego School of Medicine. “What we’ve done here is find the safety glass and identify several of its core components, which we can now explore as therapeutic targets.” 

When chromosomes break and rearrange themselves, this can initiate or exacerbate cancer in several ways. For example, if a tumor suppressor gene is broken in the process, the cell will become more vulnerable to tumor formation. In other cases, genes that aren’t usually close to each other on the chromosome can suddenly be stitched together to produce a new oncogenic fusion protein. During chromothripsis, many such changes occur simultaneously, rather than gradually, thus accelerating cancer development or its resistance to therapy.

Now that the researchers had identified an early step in this process — the tethering of shattered DNA fragments — they wondered if they could stop it. By destroying the tether, they might prevent the rearranged chromosomes from forming, thereby reducing the number of cells potentially carrying cancerous mutations.

To do this, postdoctoral fellow and first author of the study Prasad Trivedi, PhD, engineered a modified version of one of the tether proteins so that he could induce its destruction on demand. When he did so, the tether disintegrated, the DNA fragments did not cluster and the resulting cells showed reduced survival.

The authors suggest that the proteins in this tether complex, particularly cellular inhibitor of PP2A (CIP2A), may now be an attractive therapeutic target for chromosomally unstable tumors.

“The process of chromosomal care and repair contributes to cancer in many ways, so the more we understand how it works, the better we can fine-tune it to treat cancer,” said Cleveland. 

Co-authors of the study include: Christopher D. Steele, Franco K. C. Au and Ludmil B. Alexandrov, all at UC San Diego. 

The study was funded, in part, by the National Institutes of Health (grants R35 GM122476, R01ES030993-01A1, R01ES032547 and R01CA269919), the Hope Funds for Cancer Research and the Packard Fellowship for Science and Engineering.