Phenotypes in mice lacking WRN, BLM and telomerase

University Of Pennsylvania, Philadelphia PA

Investigators

Abstract

Telomere shortening accompanies but plays an uncertain causal role in human aging. Werner syndrome and, to a lesser degree, Blood syndrome are diseases characterized by premature features of aging. The syndromes are caused by loss of the RecQ-family helicases WRN and BLM, respectively. Evidence is accumulating that Werner syndrome cells have defects in the maintenance of telomeres. In S. cerevisiae, mutants in SGS1, the yeast RecQ homologue, have defects in telomere maintenance, but only in cells that lack telomerase. In mice (mus musculus), telomere shortening appears not to cause aging, but if telomerase is inactivated genetically, telomeres shorten and phenotypes eventually arise after several generations. Compared with humans, mice have longer telomeres and more abundant telomerase. Thus the telomere biology of telomerase knock-out mice is more similar to that of most human cells. Remarkably, loss of WRN and BLM are well tolerated in mice, and a possible reason for this could be the differences between murine and human telomere biology. This is supported by the critical role of SGS1 at telomeres only in yeast cells lacking telomerase. For these reasons, the roles of MRN and BLM in mice lacking telomerase will be examined. We will ask whether mice that lack telomerase (the RNA component, TER) and WRN and BLM together develop earlier, more profound or event different defects that simply lack telomerase or WRN and BLM alone. We will focus on defects that are well-established to occur in telomerase or WRN and BLM alone. We will focus on defects that are well- established to occur in telomerase knockout mice. These include 1) dysfunction in highly proliferative tissues such as the gut, epidermis and hematopoietic system, 2) gonadal atrophy and germ cell apoptosis, 3) telomere shortening and 4) WRN and BLM at human telomeres and improve understanding of the role of telomeres in human aging. Long- term possible benefits of such understanding could include treatment for age-associated diseases.