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[Cell Cycle 8:15, XXXX-XXXX; 1 August 2009]; ©2009 Landes Bioscience

Where did they come from? The origin of endogenous γ-H2AX foci in tumor cells

In our recent publication “Telomere-dependent and telomere-independent origins of endogenous DNA damage in tumor cells” (www.impactaging. com),1 we demonstrated that dysfunctional telom- eres are the major factor accounting for the variability in the amount of γ-H2AX foci in tumor cells.1 While γ-H2AX is an extremely valu- able tool to study DNA repair pathway after DNA damage induction from sources including ionizing radiation exposure and drug treatment, recently the importance of the endogenous γ-H2AX foci in mammalian aging and in carcino- genesis has also become clear. There is an abundance of evidence that tumor cells exhibit high levels of γ-H2AX foci.

However, several important questions have not been answered. What is the origin of these cryptogenic γ-H2AX foci? Why do the amounts of γ-H2AX foci vary in tumor cells? Our recent study answered these questions.

We showed that endogenous γ-H2AX foci in tumor cells are due to dysfunctional telomeric DNA damage and amounts of γ-H2AX foci inversely correlate with the telomerase activity of tumor cell lines. Our next area of interest is to determine possible applications for this new finding. Telomerase expression is one of the distinguishable characteristics between malig- nant and primary healthy cells, which makes it a quite suitable target for cancer therapy.2 Inhibiting telomerase activity in tumor cells may increase the number of damaged telomeres and thereby limit proliferation. We showed that each tumor cell line has a signature level of telomere- associated DNA damage and the amounts of this damage correlate with telomerase activity. Therefore, telomerase inhibitors or telomere maintenance-targeting drugs can affect different tumors with different intensity, and analysis of telomere-associated γ-H2AX focal numbers in primary tumors treated with telomerase-based drugs can become a general assay to monitor drug efficiency.3

In conclusion, our new finding raises the possibility that γ-H2AX could be a potential biomarker to assess which tumors are more vulnerable to telomerase inhibition and provide useful information for developing tailor-made cancer therapy.

References 1. Nakamura AJ, et al. Aging, 2009; 1:212-8. 2. Olive PL. Aging, 2009; 1:154-6. 3. Harley CB. 2008; 8:167-79

Asako J. Nakamura, Christophe E. Redon and Olga A. Sedelnikova; National Institutes of Health; Bethesda, MD; Email: nakamuraa@ mail.nih.gov

The hypoxic response and aging

Two recent papers have described a new role for the hypoxic response as a modulator of longevity and protein homeostasis. Interestingly, the way this pathway influences aging appears to be context-dependent, promoting longevity under some conditions and limiting it under others.

The hypoxic response is an evolutionarily conserved pathway that functions to maintain cellular homeostasis in the face of variable oxygen availability.1 A central player in this pathway is the hypoxia inducible transcription factor, HIF. Under conditions of high oxygen availability, the alpha subunit of HIF, HIF-1α, is hydroxylated by the prolyl hydroxylase (PH) superfamily of dioxygenase and subjected to ubiquitin mediated proteasomal degradation through the von Hippel-Lindau tumor suppressor VHL1 Under conditions of low oxygen, HIF-1α is stabilized and is able to induce expression of a variety of stress response, metabolic, and growth factor genes collectively referred to as the hypoxic response. In addition to hypoxia, HIF activity can be influenced by a number of other stimuli, including insulin-like signaling, target of rapamycin (TOR) activity, temperature, acidosis, nitric oxide, inflammation, and oxidative stress.

In a paper published April 16 in Science Express, Mehta et al.2 report a new role for the hypoxic response in aging using the nema- tode Caenorhabditis elegans. Induction of the nematode HIF-1α (HIF-1), either by mutation of VHL-1 or by growth in low oxygen is suffi- cient to increase adult life span by up to 40%. Interestingly, the hypoxic response appears to promote longevity under the conditions used by Mehta et al.2 through a mechanism that is distinct from both dietary restriction and reduced insulin- like signaling, two well-characterized pathways that modulate aging in C. elegans. In addition to enhancing life span, induction of the hypoxic response also confers resistance to amyloid beta and polyglutamine toxicity in nematode models of Alzheimer’s and Huntington’s diseases, respectively. These findings identify the hypoxic response as a previously unknown pathway for controlling longevity and protein homeostasis.

In a separate study published on May 22 in PLoS Genetics, Chen et al.3 independently observed that the hypoxic response modulates aging in C. elegans. Their results differ from Mehta et al.,2 however, in that deletion of HIF-1 is observed to increase life span at elevated temperatures (Mehta et al. examined life span at 20°C, while Chen et al. used 25°C for their experiments) in a manner overlapping with the effects of dietary restriction. Furthermore, Chen et al.3 report that animals in which HIF-1 is induced by a mutation in the EGL-9 prolyl hydroxylase fail to show full lifespan extension in response to dietary restriction. Chen et al.3 propose that HIF-1 acts in a pathway down- stream of dietary restriction and TOR to repress longevity by a mechanism involving induction of ER stress response genes. Thus, it appears that HIF-1 plays a context-dependent role in modulating longevity. Further studies will be required to understand the apparent nutrient and temperature-dependent relationship between HIF-1 activity and longevity and whether differ- ential induction of HIF-1 target genes in response to mutation of VHL-1 or EGL-9 contribute to its effects on aging.

Taken together, these two recent reports point to an important but complex relationship between the hypoxic response and aging in nematodes. They also raise the possibility that modulation of HIF-1 may be a viable therapeutic strategy for treating age-associated diseases in people. HIF inhibitors are already being studied for potential anti-cancer activities,4 and the results of Mehta et al.2 suggest that HIF activators may prove beneficial against diseases associ- ated with proteotoxic stress. Studies to further characterize the relevant downstream targets of HIF-1 that are most important for the longevity and proteotoxicity phenotypes in C. elegans are currently underway, and it will be of interest to discover whether HIF-1 and its targets play a similar function in mammalian aging.

References 1. Shen C, et al. Ann NY Acad Sci 2003; 995:191-9. 2. Mehta R, et al. Science 2009. 3. Chen D, et al. PLoS Genet 2009; 5:e1000486. 4. Semenza GL. Nat Rev Cancer 2003; 3:721-32.

Matt Kaeberlein1 and Pankaj Kapahi2; 1University of Washington, Seattle, WA; 2Buck Institute for Age Research, Novato, CA; Email: [email protected]

1 Cell Cycle 2009; Vol. 8 Issue 15