Poster Presentation 30th Lorne Cancer Conference 2018

Links between DNA replication stress and telomere extension in cancer cells (#128)

Tracy M Bryan 1 , Melissa Kartawinata 1 , Adrian S Tong 1 , Josh L Stern 1 , Amanda XY Chen 1
  1. Children's Medical Research Institute, Westmead, NSW, Australia

The ribonucleoprotein enzyme telomerase counteracts telomere shortening in germ cells, stem cells and a majority of cancers, allowing for unlimited cell division. Most normal cells do not express telomerase, so inhibition of telomerase is a promising avenue for development of specific anti-cancer treatments that should be applicable to almost all cancers. Telomerase action can be inhibited in vivo by blocking the cellular pathways that direct telomerase to chromosome ends, i.e. telomerase ‘recruitment’ to telomeres. This process is highly regulated, but factors that regulate it are incompletely understood.

We have demonstrated that telomerase recruitment to telomeres in human cells is highly dependent on the DNA damage response kinases ATM and ATR1, that together play a crucial role in safeguarding the genome. This is an unexpected finding, since in general the DNA damage response is suppressed at telomeres, suggesting that telomeres exploit DNA damage signalling pathways to bring telomerase to the telomere. ATR controls the cellular response to single-stranded DNA arising during replication fork stalling, and we also showed that replication stress increases the levels of telomerase at the telomere, in an ATR-dependent manner1. The effect of ATR on telomerase recruitment is mediated, at least in part, by its substrate Chk1, a kinase that is also critical for genomic stability during DNA replication.

We have also elucidated the downstream targets of ATM that are crucial for telomerase recruitment, including the telomeric “shelterin” proteins TPP1 and TRF1, which are responsible for positively or negatively regulating interactions of telomerase with telomeres, respectively. Together, these observations represent a new understanding of the relationship between telomerase and the DNA damage response, revealing telomerase as a specialised response to general genomic stress. Furthermore, both processes are key drivers of oncogenesis, and our data demonstrate that they are tightly linked.

  1. Tong, A.S., Stern, J.L, Sfeir, A., Kartawinata, M., de Lange, T., Zhu, X.D. and Bryan, T.M. (2015) ATM and ATR Signaling Regulate the Recruitment of Human Telomerase to Telomeres. Cell Reports, 13(8):1633-46.