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September 28, 2016

Death Switch in the Cell Is Also a DNA Repair Switch

  • To repair or not to repair, that is the question the cell must answer after suffering a genomic injury known as the double-strand break. This sort of damage may be caused by radiation, and it may lead to cancer if it is not set right. If the damage is beyond repair, the cell may choose to activate a suicide program, an alternative means of preserving the body’s integrity—but exactly how the cell decides between repair and self-slaughter has been unclear.

    According to a new paper ("E4 Ligase-Specific Ubiquitination Hubs Coordinate DNA Double-Strand-Break Repair and Apoptosis") by scientists based at the University of Cologne, the cell seems to vacillate at first. At the same time it prepares to oppose the natural shocks to which the genome is heir, it also prepares to commit suicide via apoptosis. Ultimately, however, the indecision is resolved when the cell integrates signals from both the ongoing repair process and the cell death machinery. The question—repair or death?—is settled by the workings of a previously unidentified mechanism, one involving a protein called UFD-2, or ubiquitin fusion degradation-2.

    Details of the mechanism appeared September 26 in the journal Nature Structural & Molecular Biology (NSMB). The paper described how the University of Cologne scientists, led by Thorsten Hoppe, Ph.D., identified the E4 ubiquitin ligase UFD-2 as a mediator of DNA-damage-induced apoptosis in a genetic screen in Caenorhabditis elegans.

    The scientists used different strains of C. elegans, including wild-type and genetically modified ones. All the strains were exposed to ionizing radiation to induce double-strand breaks.

    “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,” wrote the authors of the NSMB paper. “In the absence of UFD-2, RAD-51 foci persist, and DNA damage-induced apoptosis is prevented.”

    In this way, through the formation of UFD-2 complexes at double-strand breaks, the cell verifies that it should continue with repairs.

    “UFD-2 foci are retained until recombination intermediates are removed by the Holliday-junction-processing enzymes GEN-1, MUS-81 or XPF-1,” the authors continued. “Formation of UFD-2 foci also requires proapoptotic CEP-1 (p53) signaling.”

    Essentially, the UFD-2 mechanism allows the cell to arrive at a carefully considered course of action, avoiding dire outcomes that might result from a less balanced approach. If apoptosis should be necessary, but is nonetheless avoided, there is a higher risk that a damaged cell will become a cancer cell. At the same time, although apoptosis protects against cancer, excessive cell death can lead to tissue degeneration and aging.

    The current study builds on earlier work conducted by senior author Prof. Dr. Hoppe. He originally identified UFD-2 as a key regulator of protein degradation. The new results establish that there is more to UFD-2 than was previously dreamt of. UFD-2 forms regulatory centers that coordinate DNA repair and cell death.

    “The knowledge we gained from this study provides new perspectives for fighting cancer pharmaceutically,” noted Prof. Dr. Hoppe. “It might be possible to manipulate the well-balanced process of apoptosis and protein degradation to make clearance of tumor cells more efficient.”

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