2024 - Titia de Lange
Motivation
De Lange is being recognized for discovering the molecular mechanisms by which telomeres protect chromosome ends, characterizing the function of the shelterin protein complex, and demonstrating how loss of telomere protection results in aberrant genomic integrity and tumorigenesis.
De Lange’s research has brilliantly elucidated the role of telomeres—regions of repetitive nucleotide sequences at the ends of chromosomes—in cancer onset and progression, mainly through work that has defined the role of the shelterin protein complex in protecting telomeric DNA by blocking DNA damage and repair activity.
In 1995, through the use of elegant biochemistry approaches, de Lange identified and cloned the first telomeric mammalian protein of the shelterin complex (TRF1), defining its role in the inhibition of telomeric DNA elongation. Later, de Lange identified four additional shelterin complex proteins (TRF2, TIN2, Rap1, and TPP1) that, together with TRF1 and POT1, are responsible for telomere protection. Through a series of groundbreaking experiments using murine knockout models, de Lange and her collaborators characterized the fate of telomeres lacking one or more shelterin complex subunits, demonstrating that cells perceive chromosome ends as damaged DNA when shelterin is compromised, as shelterin is able to inhibit six different DNA damage response mechanisms. De Lange’s research showed that in the absence of shelterin, there is aberrant double-stranded DNA damage repair, resulting in the induction of cell death and/or cellular senescence via the ATM and ATR kinase signaling pathway.
In addition, de Lange and her collaborators made a major molecular biology discovery with the identification of the t-loop structure of telomeres, whereby a single-stranded overhang is inserted into the double-stranded repeat array of the telomere. This structure protects the telomere end from DNA damage responses, a mechanism orchestrated by TRF2.
De Lange also uncovered a potential cancer-causing mechanism with the observation that telomere shortening leads to genomic instability in cells with mutations in TP53, a gene that is mutated in half of all cancers. Given that telomere lengthening can lead to cancer, de Lange investigated and later found that the POT1, TIN2, and TRF1 shelterin complex proteins may help prevent cancer by blocking the activity of the telomere-lengthening protein telomerase.
Collectively, de Lange’s research has had direct and profound clinical implications, highlighted by one of her more recent discoveries that individuals with germline mutations in TIN2 are born with extremely long telomeres and present with an increased risk of developing cancer.
“Dr. de Lange’s pioneering research has greatly increased our understanding of how a cell responds when its DNA is damaged,” said Margaret Foti, PhD, MD (hc), chief executive officer of AACR. “Dr. de Lange is a world-renowned expert in how telomeres protect chromosome ends, and her groundbreaking research has provided crucial scientific insights into the development and progression of cancer. The Pezcoller Foundation and the AACR are thrilled to honor her with this prestigious award.”
“We are especially happy and proud that the Pezcoller Foundation-AACR International Award for Extraordinary Achievement in Cancer Research has been given this year to Dr. de Lange for her highly impactful research on telomeres that has defined the role of the shelterin protein complex in cancer initiation and progression,” said Enzo Galligioni, MD, president of the Pezcoller Foundation. “The Pezcoller Foundation, in partnership with AACR, has been recognizing the best cancer researchers with this award for more than 25 years—including three future Nobel laureates. It is notable that the research that earned Dr. de Lange this year’s prize is in telomeres. In 2001, Dr. Elizabeth Blackburn won the Pezcoller Foundation-AACR International Award for Extraordinary Achievement in Cancer Research for her trailblazing work in the same field; in 2009, she received the Nobel Prize in Physiology or Medicine for her discoveries.”
