Genetic Switch Decides Between Genome Repair and Cell Death

Summary: Researchers have identified a mechanism that integrates signals from the ongoing repair process and the cell death machinery.

Source: University of Cologne.

The genetic information of every cell is encoded in the sequence of the DNA double helix. Double strand breaks in the DNA, which can be induced by radiation, are a dangerous threat to the cells, and if not properly repaired can lead to cancer. Damaged cells need to decide whether the breaks can be fixed or whether they should be removed by a cellular suicide program called “apoptosis” before initiating cancer.

Björn Schumacher, one of the senior authors, explains: “Within seconds after an harmful incident, different mechanisms start. In a schizophrenic way, the cell starts repairing as well as preparing for apoptosis. We identified an uncharacterized mechanism that integrates signals from the ongoing repair process and the cell death machinery. A protein called UFD-2 forms large complexes at the breaks and verifies whether to proceed with the repair or whether it’s time to die.” In the process, UFD-2 is a point of intersection that both receives and gives signals.

The experiments were performed with the nematode Caenorhabditis elegans. “For our research we used different strains of C. elegans, including wild type and genetically modified ones. They were exposed to ionizing radiation to induce double strand breaks and then examined,” says Leena Ackermann, lead author of the study. Schumacher adds: “The results are important to further understand how and why a cell decides to repair or to die. Is the repair still ongoing and successful or is apoptosis necessary? Cells lacking UFD-2 fail to undergo apoptosis. In humans such a situation could lead to a higher risk of a damaged cell becoming a cancer cell.”

Image shows an idolated germ line of a C. elegans worm.

All the proteins that play a part in this mechanism can be found in humans as well, and the findings could be highly relevant to better understanding how DNA damage leads to cancer. DNA damage is also an important driver of the aging process. Although apoptosis protects from cancer, excessive cell death can lead to tissue degeneration and aging. The senior author Thorsten Hoppe originally identified UFD-2 as a key regulator of protein degradation. Here, UFD-2 forms regulatory centers that coordinate DNA repair and cell death. Hoppe hopes for resulting advances in tumor therapy: “The knowledge we gained from this study provides new perspectives for fighting cancer pharmaceutically. It might be possible to manipulate the well-balanced process of apoptosis and protein degradation to make clearance of tumor cells more efficient.”

ABOUT THIS GENETICS RESEARCH ARTICLE

Source: University of Cologne
Image Source: NeuroscienceNews.com image is adapted from the University of Cologne press release.
Original Research: Abstract for “E4 ligase–specific ubiquitination hubs coordinate DNA double-strand-break repair and apoptosis” by Leena Ackermann, Michael Schell, Wojciech Pokrzywa, Éva Kevei, Anton Gartner, Björn Schumacher and Thorsten Hoppe in Nature Structural and Molecular Biology. Published online September 26 2016 doi:10.1038/nsmb.329

University of Cologne “Genetic Switch Decides Between Genome Repair and Cell Death.” NeuroscienceNews. NeuroscienceNews, 27 September 2016.
<http://neurosciencenews.com/apoptosis-genetics-neurogenesis-5133/&gt;.

Abstract

E4 ligase–specific ubiquitination hubs coordinate DNA double-strand-break repair and apoptosis

Multiple protein ubiquitination events at DNA double-strand breaks (DSBs) regulate damage recognition, signaling and repair. It has remained poorly understood how the repair process of DSBs is coordinated with the apoptotic response. Here, we identified the E4 ubiquitin ligase UFD-2 as a mediator of DNA-damage-induced apoptosis in a genetic screen in Caenorhabditis elegans. We found that, after initiation of homologous recombination by RAD-51, UFD-2 forms foci that contain substrate-processivity factors including the ubiquitin-selective segregase CDC-48 (p97), the deubiquitination enzyme ATX-3 (Ataxin-3) and the proteasome. In the absence of UFD-2, RAD-51 foci persist, and DNA damage-induced apoptosis is prevented. In contrast, UFD-2 foci are retained until recombination intermediates are removed by the Holliday-junction-processing enzymes GEN-1, MUS-81 or XPF-1. Formation of UFD-2 foci also requires proapoptotic CEP-1 (p53) signaling. Our findings establish a central role of UFD-2 in the coordination between the DNA-repair process and the apoptotic response.

“E4 ligase–specific ubiquitination hubs coordinate DNA double-strand-break repair and apoptosis” by Leena Ackermann, Michael Schell, Wojciech Pokrzywa, Éva Kevei, Anton Gartner, Björn Schumacher and Thorsten Hoppe in Nature Structural and Molecular Biology. Published online September 26 2016 doi:10.1038/nsmb.3296

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connie dello buono

Health educator, author and enterpreneur motherhealth@gmail.com or conniedbuono@gmail.com ; cell 408-854-1883 Helping families in the bay area by providing compassionate and live-in caregivers for homebound bay area seniors. Blogs at www.clubalthea.com Currently writing a self help and self cure ebook to help transform others in their journey to wellness, Healing within, transform inside and out. This is a compilation of topics Connie answered at quora.com and posts in this site.

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