Research
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Telomeres and cancer: tumor suppression and genome instability
We are studying the genomic consequences of telomere crisis to understand how telomere shortening contributes to genome instability.
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How shelterin solves the end-protection problem
The multi-subunit shelterin complex is crucial for the protection of telomeres from the DNA damage response and regulates telomere maintenance by telomerase.
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Generation and maintenance of telomere ends
The protection of telomeres is in part dependent on the presence of a 3’ overhang at the telomere terminus. This overhang has to be regenerated every time telomeres are duplicated. The process of 3’ overhang formation is carefully controlled by shelterin.
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TRF1 promotes telomere replication and prevents formation of fragile telomeres
TRF1 functions to promote efficient replication of telomeric DNA. In absence of TRF1, replication fork stalling occurs in telomeric DNA tracts and the ATR kinase pathway is activated at telomeres.
Reviews
Z. Mirman & T. de Lange (2020) 53BP1: a DSB escort. Genes Dev. 34: 7-23.
T. de Lange (2018) Shelterin-mediated telomere protection. Ann. Rev. Genetics 52:223-247.
T. de Lange (2018) What I got wrong about shelterin. J. Biol. Chem. 293: 10453-10456.
J. Maciejowski & T. de Lange (2017) Telomeres in cancer: tumour suppression and genome instability. Nat Rev Mol Cell Biol 18: 175-186.
I. Schmutz & T. de Lange (2016) Shelterin. Curr Biol. 26: R397-399.
T. de Lange (2015) A loopy view of telomere evolution. Front. Genet. 6:321.
Current research support (PI de Lange):
NIH RO1 AG16642; Mechanism of the telomeric proliferation limit. 4/1/99-8/31/20
NIH RO1 1R35CA210036; Genome instability in cancer: telomeres and DNA repair. 9/2/16- 8/31/23
Breast Cancer Research Foundation; Genome instability and the onset of breast cancer. 10/1/03 to 09/30/20
Starr Cancer Consortium I13-0019; The role of telomerase in healing broken chromosomes in cancer. 1/1/20 to 12/31/21
Melanoma Research Alliance 577521; Telomere crisis in acral melanoma: diagnostic and prognostic potentials. 6/1/18 to 5/31/21