Researchers found new type of repair used by telomeres to form new DNA

(Philadelphia) – Maintaining the ends of chromosomes, called telomeres, allows cells to continuously divide and achieve immortality. In a new study published this week in Nature, senior author Greenberg and colleagues have developed a first-of-its- kind system to observe repair to broken DNA in newly synthesized telomeres, an effort which has implications for designing new cancer drugs.

Telomeres stay intact in most cancer cell types by means of a specialized enzyme called telomerase that adds the repetitive telomere DNA sequences to the ends of chromosomes. Cancer cells can also use a second method involving a DNA-repair-based mechanism, called alternative lengthening of telomeres, or ALT for short. In general, cancer cells take over either type of telomere maintenance machinery to become immortal. Overall, about fifteen percent of cancers (those of cartilage, bone, and brain, for example) use the ALT process for telomere lengthening and maintenance.

When DNA breaks, it triggers DNA repair proteins like the breast cancer suppressor proteins BRCA1 and BRCA2 into action, along with other helper proteins, that attach to the damaged stretch of DNA. These proteins stretch out the DNA, allowing it to be recognized by complementary sequences of telomere DNA. In general, this mechanism, called homologous recombination, happens when DNA building blocks are exchanged between two nearly identical molecules of DNA.

In the current Nature study, the team found that telomeres use a unique type of repair to make new DNA, which they call “break-induced telomere synthesis.” The team found that the homologous recombination for telomeres was different from other forms of homologous recombination that involve BRCA1, 2 and Rad51 proteins, which are mutated in people with breast cancer and at risk for breast cancer.

“This is what we want to stop in cancer cells, but it has not been possible to directly follow the process while it is happening” Greenberg said. “This is the first study to follow all of the major steps of homologous recombination in real time. Now there is a possibility that because we know this process better, different points in the process could be interfered with to keep telomeres in cancer cells from continually lengthening. This may push them over the edge to cell death.”,” Greenberg said.

Citation: Break-induced telomere synthesis underlies alternative telomere maintenance.
Authors: Robert L. Dilley, Priyanka Verma, Nam Woo Cho, Harrison D. Winters, Anne R. Wondisford & Roger A. Greenberg.
DOI: http://dx.doi.org/10.1038/nature20099
Journal: Nature
Research funding: National Institutes of Health, Abramson Family Cancer Research Institute, Basser Research Center for BRCA
Adapted from press release by University Pennsylvania School of Medicine

Understanding Leukemia cell movement gives clues to its resistance to treatment

This is a high-resolution render of unique environments in the bone marrow (blue,
purple and green) as they are invaded and populated by leukemia cells (yellow).
Credit: Edwin Hawkins and Delfim Duarte/Imperial College London

New research is shedding light on how leukaemia cells can survive cancer treatment, suggesting new possibilities for stopping them in their tracks. Leukaemia has one of the highest cancer mortality rates. This is partly because there is a high relapse rate, as some cancer cells can survive the initial treatment. These surviving cells are often resistant to treatment, allowing the cancer to spread and become fatal. These findings were published in Nature.

How these treatment-resistant cells survive initial chemotherapy is not well understood. One popular theory has been that they sit hiding in specific niches within the bone marrow that usually harbour blood stem cells – basic cells that can become all other blood cells.

However, new research in mice, and validated with human samples, has revealed that certain leukaemia cells do not sit and hide. The research was led by a team at Imperial College London with colleagues from the Francis Crick Institute in London and the University of Melbourne in Australia, and is published today in Nature. Instead, to the researchers’ surprise, the cells were scattered throughout the mouse bone marrow both before and after treatment, and they were moving around rapidly.

After treatment, the leukaemia cells that survived were seen moving faster than those before treatment. The researchers suggest that the act of moving itself may help the cells to survive, possibly through short-lived interactions with an array of our own cells.

The team’s investigation into leukaemia cells’ behaviour also revealed that they actively attack bone cells, which are known to support healthy blood production. The researchers believe this insight could help scientists to develop treatments to safeguard production of healthy blood cells in leukaemia patients.

To investigate the working of leukaemia at the cellular level, the team used a technique called intravital microscopy that allows high-resolution fast imaging of live animals. The team used mice with a particularly deadly type of leukaemia called T cell acute leukaemia and tracked the movement of disease cells before and after treatment.

The research was funded by the charities Bloodwise and Cancer Research UK, alongside contributions to buy equipment and recruit team members from the European Research Council, the Human Frontier Science Program, and the European Hematology Association.

Publication: T-cell acute leukaemia exhibits dynamic interactions with bone marrow microenvironments.
DOI: http://dx.doi.org/10.1038/nature19801
Authors: Edwin D. Hawkins et.al.,
Research funding: Bloodwise, Cancer Research UK, European Research Council, Human Frontier Science Program, and European Hematology Association.
Adapted from press release by Imperial College London