Telomeres and cancer: tumor suppression and genome instability
Lab members investigating Telomeres and Cancer: Alex Stuart and Charlie Kinzig
Human telomeres can be maintained by telomerase, but most normal human cells lack (sufficient) telomerase and experience gradual telomere shortening. Eventually, the shortened telomeres become too short to fulfill their protective function, resulting in a block to further proliferation and a finite replicative lifespan. The critically short telomeres activate the DNA damage response (DDR), which induces cell cycle arrest and senescence or apoptosis, depending on the cellular context. This programmed proliferation barrier was long thought to function as a tumor suppressor pathway, a notion we recently confirmed based on cancer-prone families with mutations in TIN2.
We showed that TIN2 is a haplo-insufficient tumor suppressor that limits telomere length at birth. Telomere shortening can only act as an effective tumor suppressor pathway if telomeres are not too long at birth. Mutations in the shelterin components TIN2 (shown by us) and POT1 (shown by others) result subjects with excessively long telomeres that are highly cancer prone. The work on the TIN2 and POT1 families demonstrate the protective power of the telomere tumor suppressor pathway in preventing cancer in many different tissues.
Despite the telomere tumor suppressor pathway, cancer can develop when incipient cancer cells lose the p53/Rb pathways. Such cells ignore the cell cycle arrest signals and their telomeres shorten further during additional cell divisions. Eventually, the burden of dysfunctional telomeres leads to telomere-telomere fusions and formation of dicentric chromosomes. This stage of tumor development is referred to as telomere crisis and is thought to be an important source of genome instability in cancer. Eventually, patent cancer will only arise from cells that escape telomere crisis by upregulation of telomerase or activation of the ALT pathway. We are studying the genomic consequences of telomere crisis to understand how telomere shortening contributes to genome instability.
Our work has illuminated that the persistent DNA damage signal associated with telomere dysfunction can drive endoreduplication and formation of tetraploid cells. Tetraploidization is a hallmark of a large fraction of human cancers and our work suggest that some of cancers have become tetraploid as a consequence of their past telomere crisis. We have also found that the dicentric chromosomes formed in telomere crisis can fuel chromothripsis (chromosome shattering) and kataegis (hyper mutation clusters). Unlike what was previously believed, we showed that dicentric chromosomes can persist through mitosis and form long chromatin bridges between daughter cells. These bridges are attacked by a cytoplasmic nuclease, TREX1, which accesses the bridge DNA after transient rupture of the nuclear envelope. TREX1 digestion leads to extensively fragmented ssDNA that joins the daughter nuclei after bridge resolution. The fragmented DNA is joined haphazardly leading to the chromothriptic patterns that are accompanied by kataegis due to APOBEC editing of the single stranded DNA.
Publications since 2010:
S.M. Dewhurst, X. Yao, J. Rosiene, H. Tian, J. Behr, N. Bosco, K.K. Takai, T. de Lange and M. Imieliński (2021) Structural variant evolution after telomere crisis. Nat Commun 12:2093.
K. Hadi et al. (2020) Distinct Classes of Complex Structural Variation Uncovered across Thousands of Cancer Genome Graphs. Cell 183: 197-210.e32.
C.A. Lovejoy, K. Takai, M.S. Huh, D.J. Picketts & T. de Lange (2020) ATRX affects the repair of telomeric DSBs by promoting cohesion and a DAXX-dependent activity. PLoS Biol 18: e3000594.
J. Maciejowski, A. Chatzipli, A. Dananberg, K. Chu, E. Toufektchan, L.J. Klimczak, D.A. Gordenin, P.J. Campbell and T. de Lange. (2020) APOBEC3-dependent kataegis and TREX1-driven chromothripsis during telomere crisis. Nat Genet 52: 884-890.
I. Schmutz, A.R. Mensenkamp, K.K. Takai, M. Haadsma, L. Spruijt, R.M. de Voer, S.S. Choo, F.K. Lorbeer, E.J. van Grinsven, D. Hockemeyer, M.C. Jongmans and T. de Lange (2020) TINF2 is a haploinsufficient tumor suppressor that limits telomere length. Elife 9:e61235
J. Maciejowski & T. de Lange (2017) Telomeres in cancer: tumour suppression and genome instability. Nat Rev Mol Cell Biol 18: 175-186.
J. Maciejowski, Y. Li, N. Bosco, P.J. Campbell & T. de Lange (2015) Chromothripsis and Kataegis Induced by Telomere Crisis. Cell 163: 1641-1654.
C.A. Lovejoy et al. For the ALT Starr Cancer Consortium. (2012) Loss of ATRX, genome instability, and an altered DNA damage response are hallmarks of the Alternative Lengthening of Telomeres pathway. PLoS Genetics 8:e1002772 * corresponding author.
T. Davoli and T. de Lange (2012) Telomere-driven tetraploidization occurs in human cells undergoing crisis and promotes transformation in mouse cells. Cancer Cell 21: 765-776.
T. Davoli & T. de Lange (2011) The Causes and Consequences of Polypolidy in Normal Development and Cancer. Annu. Rev. Cell Dev. Biol, 27: 585-610
T. Davoli, E. Lazzerini Denchi, T. de Lange (2010) Persistent Telomere Damage Induces Bypass of Mitosis and Tetraploidy. Cell 141: 81-93.