Lecture Prof. Claus M. Azzalin

TERRA and telomere transcription: crossing boundaries between cancer and aging.

Prof. Claus M. Azzalin 

Institute of Biochemistry (IBC), Eidgenossische Technische Hochschule Zurich (ETHZ), Zurich, CH-­‐8093, Switzerland 

It is now clearly established that the long noncoding RNA TERRA (TElomeric Repeat-­‐containing RNA) is an integral component of eukaryotic telomeric heterochromatin. Our laboratory has reported that in order to maintain telomere length, telomerase-­‐negative human cancer ALT cells rely on RNA:DNA hybrids formed by TERRA and the C-­‐rich strand of the telomeric DNA array. In fission yeast, we have now found that polyadenylated  TERRA  species,  generated  either  spontaneously  from  shortened  telomeres  or  through  experimental  induction,  promote  telomere  elongation  by physically  interacting  with  telomerase  and  stimulating  its  association  with  the  transcribing  chromosome  end.  We  have  also  discovered  that  TERRA  transcription accelerates telomere shortening in fission yeast and human cells lacking telomerase, thereby anticipating senescence onset. Therapeutic targeting of TERRA has therefore the  potential  delay  cellular senescence and  thus  age-­‐associated  morbidities,  while  concomitantly preventing  cancer  development  through  suppression  of  telomere lengthening mechanisms.

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