In mice, telomerase deficiency results in a segmental progeria that increases in intensity over the generations, as the telomeres grow shorter; in humans, similar mutations can result in the syndrome known as dyskeratosis congenita, whose symptoms include bone marrow failure. Mismatch repair defects results in increased cancer incidence (in humans, especially colon tumors). Both types of mutation dramatically decrease lifespan.
In combination, however, these mutations actually improve longevity. Siegl-Cachedenier et al. (from Maria Blasco’s lab) bred mice that homozygously lacked telomerase subunit Terc2, the MutL homolog PMS2, or both genes at once. The double mutants lived significantly longer — not just longer than either parental mutant, but longer than the wildtype. Furthermore, the increased cancer incidence of PMS2-/- was mitigated by the Terc2-/- background (progressively more strongly in subsequent generations); conversely, the prevalence of intestinal lesions in telomerase knockouts — thought to be a result of stem cell exhaustion — was significantly diminished in the mismatch repair mutant.
How could this be? After clearing away some potential trivial explanations — PMS2-/- does not rescue the accelerated telomere shortening, formation of DNA damage foci, or telomeric recombination that characterize the Terc2-/- mutant — the authors observed that the mismatch repair mutation rescued defects in proliferation (but not the increase in apoptosis) seen in the telomerase knockout. They therefore propose that diminished induction of p21 by telomere shortening could explain the improved phenotype of the double-mutant mice:
Importantly, PMS2 deficiency rescued cell proliferation defects but not apoptotic defects in vivo, concomitant with a decreased p21 induction in response to short telomeres. The proliferative advantage conferred to telomerase-deficient cells by the ablation of PMS2 did not produce increased tumors. Indeed, Terc2-/-/PMS2-/- mice showed reduced tumors compared with PMS2-/- mice, in agreement with a tumor suppressor role for short telomeres in the context of MMR deficiencies. These results highlight an unprecedented role for MMR in mediating the cellular response to dysfunctional telomeres in vivo by attenuating p21 induction.
In other words, the decrease in p21 activity rescued the loss in proliferative potential that would ordinarily result from telomerase deficiency, thereby increasing regenerative capacity and slowing age-related decline in tissue function. Because the mismatch repair mutation did not decrease apoptosis, however, the increased proliferative potential did not result in tumor formation.
These results are is in stark contrast to other situations in which multiple DNA metabolism defects are present in the same organism (see our earlier article, How premature aging resembles calorie restriction, for a discussion of the severe progeria that occurs when multiple nucleotide excision repair mutations are combined in the same mouse).
Another striking contrast with earlier paradigms: We’ve seen numerous examples of tradeoffs between tumor prevention and tissue regeneration, usually in situations where increased activity of a tumor suppressor resulted in diminished regenerative capacity. Here, however, we see a case where two different antitumor mechanisms “cancel each other out” to give both improved tissue regeneration and diminished cancer risk. How many other winning combinations are hiding out there?