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May 2011

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Protecting telomeres involves HipHop protein

By Jeffrey Stumpf
May 2011

Yikang Rong, Ph.D.

Rong answered questions from the many interested NIEHS researchers. Rong is head of the NCI Eukaryotic Genome Maintenance Unit. (Photo courtesy of Steve McCaw)

Hemakumara Mutra, Ph.D.

Mutra moderated questions for Rong's seminar. Mutra represented fellow LMG postdoctoral trainees in hosting Rong's visit to NIEHS. (Photo courtesy of Steve McCaw)

Geneticist Yikang Rong, Ph.D., a senior investigator at the National Cancer Institute, presented evidence during an April 11 talk at NIEHS that explained models for maintaining telomeres in the fruitfly, Drosophila melanogaster. Rong's presentation, part of the Laboratory of Molecular Genetics (LMG) trainee-invited seminar series, discussed the role of the novel protein HipHop in telomere maintenance in somatic and sperm cells.

Telomeres are the ends of chromosomes that protect the integrity of DNA within the chromosomes. Loss of telomeres causes fusion of chromosome ends by DNA repair proteins, triggering cell death. To prevent telomere loss, two processes are important: the elongation of the chromosome ends - by telomerase in humans - and capping of the ends to prevent their immediate degradation.

Unlike many organisms, Drosophila does not use specific sequences to mark the location for capping telomeres, but rather can cap telomeres at any DNA double-strand break, creating new telomeres. However, the requirement for sequence-specific capping could be a misleading difference because, as Rong pointed out, the mechanism of telomere capping may be similar throughout eukaryotes. "I have no problem believing that at the end of the day, organisms cap telomeres in the same way," Rong speculated. "It doesn't seem reasonable to have to reinvent the wheel."

Drosophila offers enormous advantages in studying telomere biology, because telomere elongation and end capping are naturally uncoupled and can be studied separately. Also, Drosophila genetics has been widely used for studying many pathways in developmental and cell biology. Rong is responsible for further empowering Drosophila geneticists with his important contributions to developing gene targeting methods for site-specific mutations in Drosophila.

LMG Visiting Fellow Hemakumara Mutra, Ph.D., who hosted Rong's visit to NIEHS, also studies telomeres in Drosophila. He notes that, like Drosophila, cancer cells lack telomerase and can escape from cell death using alternate telomere lengthening mechanisms. "Studying telomere length homeostasis in Drosophila will give us insight into the telomere length maintenance during disease conditions in humans," said Mutra.

The proteins at the ends justify the means

The structure of telomere caps in Drosophila is poorly understood. Rong's strategy was to search for proteins that bind to telomere targeted proteins, called HP1 and HOAP, leading to the identification of HipHop. Similar to HOAP, reducing HipHop levels in Drosophila causes loss of telomeres, as evidenced by chromosome fusions.

Although HipHop and HOAP could be detected at telomeres, it is difficult to resolve how close to the ends the proteins bind, because the end of the chromosome contains repeated sequences. Rong's group cleverly engineered flies whose telomeres were closer to the centromere in regions where the sequence was not repeated. These experiments demonstrated a region 11 kilobases from the end to which the telomeric proteins bind, regardless of the sequence.

Sperm telomeres are maintained by HipHop's distant cousin

In the Drosophila melanogaster, there is a gene duplication of hiphop called κ81, which has testis-specific expression. Male mutants of κ81 are sterile but not because they make defective sperm. Sperm from κ81 mutants are functional, but resulting embryos die immediately after fertilization and exhibit chromosome fusions.

HipHop and K81 have similar sequences allowing K81 to be able to substitute for HipHop, although the opposite is not true. Rong's group mapped the crucial stretch of four amino acids that differ between the two proteins and are necessary for K81 function.

Rong explained the model that κ81 marks the location of telomeres during sperm formation. The paternal genome must be repackaged after fertilization and requires κ81 to prevent the embryo from processing telomeres as normal double strand breaks. This epigenetic marking of DNA is a novel mechanism of repackaging paternal genomes and may contribute to the understanding of male fertility.

(Jeffrey Stumpf, Ph.D., is a postdoctoral fellow in the NIEHS Laboratory of Molecular Genetics Mitochondrial DNA Replication Group.)

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