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New study reveals an unexpected survival mechanism for a subset of cancer cells



  New study reveals an unexpected survival mechanism for a subset of cancer cells
Metaphase chromosomes from ALT cancer cells (U2OS osteosarcoma cell line) depleted of FANCM. Telomeric DNA is in green, chromosomal DNA is in red. The arrowheads point to telomeric DNA dissociated from chromosomes, indicating severe telomeric dysfunction. Credit: Bruno Silva

Embedded at the ends of chromosomes are structures called telomeres which in normal cells become shorter as the cells divide. Progressive abbreviation triggers cell proliferation arrest or death. Cancer cells adopt different strategies to overcome this control mechanism that keeps track of the number of times a cell has divided. One of these strategies is the alternative extension of the telomer (ALT) pathway, which guarantees unlimited proliferation capacity.

Now, a research group led by Claus M. Azzalin at the Instituto de Medicina Molecular João Lobo Antunes (iMM, Portugal) discovered that a human enzyme called FANCM (Fanconi anemia, complementing group M) is required for ALT's survival tumor cells. The results are published in open access journal Nature Communications . Future strategies directed at the activity of this molecule in ALT tumor cells could provide the basis for a new therapeutic protocol for the treatment of these tumors. ALT tumors comprise approx. 1

0 percent of human tumors and often develop in children (eg in juvenile osteosarcoma) and are particularly resistant to conventional chemotherapy. "Unlike the canonical telomerase extension mechanism that activates the enzyme telomerase, these tumor cells specifically use this alternative pathway, which is insensitive to therapeutic methods based on telomerase inhibition," explains Claus M. Azzalin, group leader at iMM. Previous studies have shown that sustained physiological telomere damage must be maintained in these cells to promote telomer extension. This scenario implies that telomeric damage levels are maintained within a certain threshold high enough to trigger telomer extension but not too high to induce cell death, "said Bruno Silva, first author of the study.

Using a series of experiments based on molecular biology, cell biology and biochemistry, the research group found a crucial role for FANCM, a component of DNA damage repair machinery. "What we have found is that ALT cells require FANCM activity to prevent telomer instability and thus cell death, "Bruno Silva says." When we remove FANCM from ALT tumor cells, telomeres become severely damaged and the cells stop sharing and die very quickly. This is not observed in tumor cells expressing telomerase activity or in healthy cells, which means that it is a special feature of ATL tumor cells, "explains Claus M. Azzalin.

" In our opinion, this is very exciting because it suggests that the transient drug of FANCM activity in ALT cells should lead to very rapid cell death specifically in these cells and set the potential basis for an alternative therapeutic protocol for this type of tumor, "adds Claus Azzalin.


Scientists find mechanisms to avoid telomer instability found in cancer and aging cells


More Information:
Bruno Silva, Richard Pentz, Ana Margarida Figueira, Rajika Arora, Yong Woo Lee, Charlotte Hodson, Harry Wischnewski, Andrew J. Deans and Claus M. Azzalin (2019) FANCM restricts ALT activity by limiting telomeric replication stress induced by deregulated BLM and R-loops. Nature Communication . DOI: 10.1038 / s41467-019-10179-z

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New study reveals an unexpected survival mechanism for a subset of cancer cells (2019, May 28)
May 29, 2019
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