Highly diverse cancers share one trait—the capacity for endless cell division. Unregulated growth is due in large part to the fact that tumor cells can rebuild protective ends of their chromosomes, which are made of repeated DNA sequences and proteins. Normally, cell division halts once these structures, or telomeres, wear down. But cancer cells keep on going by deploying one of two strategies to reconstruct telomeres.

One strategy, which occurs in about 90% of cancers, requires increased production of a telomere-elongating enzyme called telomerase. A less-understood strategy, employed by the remaining 10% to 15% of cancers, is referred to as alternative lengthening of telomeres (ALT). Previously, biologists knew ALT existed simply because tumor cells could rebuild long, albeit unkempt-looking telomeres without telomerase. How they did it remained a mystery.

Now scientists in the laboratory of Jan Karlseder, PhD, of the Salk Institute for Biological Studies in La Jolla, California, have reported the first experimental induction of an ALT telomere-building program in human cells. That discovery, reported in Nature Structural and Molecular Biology (2014; doi:10.1038/nsmb.1725), positions them to target factors driving ALT-dependent cancer cell growth.

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“People have been targeting telomerase as a potential cancer therapy for a long time,” Karlseder said, noting that antitelomerase drugs are in phase 2 clinical trials against several cancers. “But mouse studies show that when you suppress telomerase, cells can upregulate ALT. That makes it absolutely critical to develop ways to block ALT.”

To learn how cells switch on ALT, the group experimentally eliminated two proteins, ASF1a and ASF1b, in normal lung cells and in a cancer cell line that relies on telomerase for immortality. ASF1 proteins are molecular chaperones, meaning they guide more glamorous proteins to their proper cellular venue. ASF1 in fact chaperones a histone protein, which, when coiled in a complex with DNA, forms the basic structural building block of DNA called a nucleosome.

The team observed a relative scarcity of nucleosomes at telomeres from ASF1-depleted cells, as one might expect once a histone chaperone is lost. They also found that ASF1-depleted cancer cells switched off telomerase but continued to thrive, meaning that tumor cells can exploit either strategy for elongating telomeres.

Most significantly, microscopy showed that nuclei of ASF1-depleted cells contained aggregates of telomeric DNA, known as PML bodies. PML bodies, so named because they were first observed in promyelocytic leukemia tumor cells, are a hallmark of ALT-dependent cancers. “Massive PML body formation in normal cells was unexpected,” said first author Roddy O’Sullivan, PhD. “It was our first clue that ASF1 loss induces ALT.”

The development of ALT inhibitors is in its infancy. This study now provides a way to construct and evaluate anticancer reagents targeting the ALT/ASF1 pathway.