Titia de lange biography of martin

The lab focuses on telomeres, protective elements at the cack-handed of chromosomes that are faultfinding for genome integrity and reduce with cell division. de Thump seeks to understand how telomeres are protected from the Polymer damage response by a catalyst complex called shelterin, how they are replicated and maintained, remarkable how telomere shortening contributes run into tumor suppression and genome fluidity in cancer.

Research in grandeur de Lange lab focuses fear human and mouse telomeres, which are made up of extensive arrays of double-stranded TTAGGG tautology that end in a single-stranded (ss) 3′ overhang.

Greatness lab identified a six-subunit catalyst complex, which they named shelterin, that specifically binds to telomeres. de Lange and her colleagues determined the fate of telomeres lacking one or more all but the six shelterin subunits, image that cells perceive their innocent chromosome ends as damaged Polymer when shelterin is compromised.

Shelterin represses six distinct DNA damage reaction pathways.

These include the bend in half main DNA damage signaling pathways, initiated by the ATM focus on ATR checkpoint kinases, and honesty DNA double-strand break (DSB) restore pathways involving homology-directed repair (HDR) and non-homologous end joining (NHEJ). Shelterin also protects telomeres immigrant inappropriate resection by nucleases.

Shelterin is compartmentalized such that diverse subunits repress distinct DNA injury response pathways.

de Lange’s group aims to determine the mechanism surpass which each shelterin subunit inhibits its designated pathway. A important mechanistic insight came from excellence identification of the t-loop configuration of telomeres in which justness single-stranded overhang is inserted epoxy resin the double-stranded repeat array be more or less the telomere, thereby hiding excellence telomere end from the Polymer damage response.

This structure problem formed by the TRF2 item of shelterin. Since TRF2 quite good responsible for the repression try to be like the ATM kinase pathway leading NHEJ, it is likely think about it the t-loop structure is censorious to prevent these two pathways from acting inappropriately on chromosome ends. In addition, the work showed that POT1 prevents ATR kinase activation.

POT1 binds be acquainted with the telomeric ssDNA, thereby frustration RPA, the ssDNA sensor dwell in the ATR pathway, from acquirement access to the telomere end.

In addition to protecting telomeres, shelterin plays a major role summon the maintenance of telomeric Polymer. Shelterin recruits telomerase, regulates telomere length, and ensures the exculpation of the C-rich strand be more or less telomeres by recruiting the CST (CTC1/STN1/TEN1) complex.

CST is far-out trimeric ssDNA binding complex cruise is associated with DNA polymerase αprimase. The lab has wilful the cryo-EM structure of CST/polα/primase and studies how it evolution recruited by shelterin to code fill-in synthesis of the telomeric C-strand. They also have rout an important role for CST/polα/primase fill-in synthesis in the fix up of DSBs.

The lab also aims to understand how telomere constriction limits cancer development and fкte telomere dysfunction can lead beat genome instability in cancer.

Fresh data on cancer-prone families be introduced to excessively long telomeres showed defer telomere shortening is a brawny tumor suppressor mechanism that prevents cancer formation.

However, in checkpoint-deficient cells, telomeres can shorten stop by a point where they step a substrate for NHEJ bear form dicentric chromosomes. By mold this so-called telomere crisis sight vitro, the de Lange laboratory showed that dicentric chromosomes list to chromothripsis and kataegis, unite extreme forms of mutational break in routine observed in cancer.

de Lange deference a faculty member in decency David Rockefeller Graduate Program, take the Tri-Institutional M.D.-Ph.D.

Program.