Cancer cells use self-inflicted DNA breaks to evade growth limits imposed by genotoxic stress.
Saved in:
| Title: | Cancer cells use self-inflicted DNA breaks to evade growth limits imposed by genotoxic stress. |
|---|---|
| Authors: | Larsen, Brian D., Benada, Jan, Yung, Philip Yuk Kwong, Bell, Ryan A. V., Pappas, George, Urban, Vaclav, Ahlskog, Johanna K., Kuo, Tia T., Janscak, Pavel, Megeney, Lynn A., Elsässer, Simon J., Bartek, Jiri, Sørensen, Claus S. |
| Source: | Science (pre-March 2025). 4/29/2022, Vol. 376 Issue 6592, p476-483. 8p. 3 Diagrams, 1 Graph. |
| Subjects: | Genetic toxicology, Radiation, Cancer treatment, Tumors, DNA |
| Abstract: | Genotoxic therapy such as radiation serves as a frontline cancer treatment, yet acquired resistance that leads to tumor reoccurrence is frequent. We found that cancer cells maintain viability during irradiation by reversibly increasing genome-wide DNA breaks, thereby limiting premature mitotic progression. We identify caspase-activated DNase (CAD) as the nuclease inflicting these de novo DNA lesions at defined loci, which are in proximity to chromatin-modifying CCCTC-binding factor (CTCF) sites. CAD nuclease activity is governed through phosphorylation by DNA damage response kinases, independent of caspase activity. In turn, loss of CAD activity impairs cell fate decisions, rendering cancer cells vulnerable to radiation-induced DNA double-strand breaks. Our observations highlight a cancer-selective survival adaptation, whereby tumor cells deploy regulated DNA breaks to delimit the detrimental effects of therapy-evoked DNA damage. [ABSTRACT FROM AUTHOR] |
| Copyright of Science (pre-March 2025) is the property of American Association for the Advancement of Science and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) | |
| Database: | Psychology and Behavioral Sciences Collection |
|
Full text is not displayed to guests.
Login for full access.
|
|
| Abstract: | Genotoxic therapy such as radiation serves as a frontline cancer treatment, yet acquired resistance that leads to tumor reoccurrence is frequent. We found that cancer cells maintain viability during irradiation by reversibly increasing genome-wide DNA breaks, thereby limiting premature mitotic progression. We identify caspase-activated DNase (CAD) as the nuclease inflicting these de novo DNA lesions at defined loci, which are in proximity to chromatin-modifying CCCTC-binding factor (CTCF) sites. CAD nuclease activity is governed through phosphorylation by DNA damage response kinases, independent of caspase activity. In turn, loss of CAD activity impairs cell fate decisions, rendering cancer cells vulnerable to radiation-induced DNA double-strand breaks. Our observations highlight a cancer-selective survival adaptation, whereby tumor cells deploy regulated DNA breaks to delimit the detrimental effects of therapy-evoked DNA damage. [ABSTRACT FROM AUTHOR] |
|---|---|
| ISSN: | 00368075 |
| DOI: | 10.1126/science.abi6378 |
