How cancer cells assure immortality by lengthening the ends of chromosomes

October 1, 2014

Alternative lengthening of telomeres (ALT) process. When a cancer cell’s DNA breaks, the cell triggers DNA repair and helper proteins to attach to the damaged stretch of DNA and stretch it out, allowing it to search and capture complementary sequences of telomere DNA to use as a template for repair. (Credit: N. W. Cho et al./Cell)

On Sept. 23, KurzweilAI noted that scientists at the Salk Institute had discovered an on-and-off “switch” in cells that might allow for increasing telomerase, which rebuilds telomeres at the ends of chromosomes to keep cells dividing and generating.

We also noted that cancer cells hijack this process and that the scientists expect that the “off” switch might help keep telomerase activity below this threshold.

Now in another study published last week in Cell, Roger Greenberg, MD, PhD, associate professor of Cancer Biology in the Perelman School of Medicine at the University of Pennsylvania and his colleagues describe their discovery of a second method used by cancer cells to survive, involving a DNA-repair-based mechanism called “alternative lengthening of telomeres” (ALT).

The researchers found that approximately 15 percent of cancers use the ALT process for telomere lengthening, but that some cancer types use ALT up to 40 to 50 percent of the time.

How the ALT process lengthens telomeres

Visualization of telomeres reeled in like fish to help repair broken cancer DNA (credit: Lili Guo, Roger Greenberg, and Nam Woo Cho, Perelman School of Medicine, University of Pennsylvania)

The team showed that when a cancer cell’s DNA breaks, the cell triggers DNA repair proteins (like the breast cancer suppressor protein 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 search for complementary sequences of telomere DNA.

“This process of repair triggers the movement and clustering of telomeres like fish being reeled toward an angler,” explains Greenberg.

“The broken telomeres use a telomere on a different chromosome — the homologous telomere — as a template for repair.” In cancer cells that use ALT to maintain their telomeres, the team visualized these clusters of telomeres coming together.

“We are very excited about the data as it has provided new insights into this mechanism of telomere maintenance and ways to think about BRCA dependent and independent DNA recombination,” he says. “But, as with most scientific studies, many more questions are raised than answers provided.”

Penn Medicine | Greenberg — chromosome ends

The team would now like to find other proteins involved in ALT and look for small-molecule drugs that target this telomere maintenance mechanism in cancer cells to selectively kill cancer types that use ALT.

This study was funded by the National Cancer Institute, the National Institute for General Medical Sciences, the Abramson Cancer Research Institute, and the Basser Research Center for BRCA. Greenberg is also an associate investigator at the Abramson Family Cancer Research Institute and director of Basic Science for the Basser Research Center for BRCA.

* Breast cancer is linked to mutations in the BRCA1 and BRCA2 genes and mutations in several genes involved in BRCA-related pathways have also been associated with breast cancer susceptibility. Breast and ovarian cancers are associated with a breakdown in the DNA repair systems involving these BRCA and other related proteins.

Abstract of Interchromosomal Homology Searches Drive Directional ALT Telomere Movement and Synapsis paper

Telomere length maintenance is a requisite feature of cellular immortalization and a hallmark of human cancer. While most human cancers express telomerase activity, ∼10%–15% employ a recombination-dependent telomere maintenance pathway known as alternative lengthening of telomeres (ALT) that is characterized by multitelomere clusters and associated promyelocytic leukemia protein bodies. Here, we show that a DNA double-strand break (DSB) response at ALT telomeres triggers long-range movement and clustering between chromosome termini, resulting in homology-directed telomere synthesis. Damaged telomeres initiate increased random surveillance of nuclear space before displaying rapid directional movement and association with recipient telomeres over micron-range distances. This phenomenon required Rad51 and the Hop2-Mnd1 heterodimer, which are essential for homologous chromosome synapsis during meiosis. These findings implicate a specialized homology searching mechanism in ALT-dependent telomere maintenance and provide a molecular basis underlying the preference for recombination between nonsister telomeres during ALT.