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The lab studies telomeres, protective elements at the ends of chromosomes that are critical for genome integrity and shorten with cell division. de Lange seeks to understand how telomeres are protected by a protein complex called shelterin, how they are replicated and maintained, and how telomere loss contributes to genome instability in cancer. The lab also studies DNA double-strand break repair with emphasis on the function of two critical DNA repair proteins, BRCA1 and 53BP1.

Research in the de Lange lab focuses on human and mouse telomeres, which are made up of long arrays of double-stranded TTAGGG repeats that end in a single-stranded 3′ overhang. The lab identified a six-subunit protein complex, which they named shelterin, that specifically binds to telomeres. Using genetic approaches, de Lange and her colleagues determined the fate of telomeres lacking one or more of the six shelterin subunits. The results showed that cells lacking shelterin perceive their natural chromosome ends as sites of DNA damage, leading to DNA damage signaling and inappropriate repair.

Shelterin represses six distinct DNA damage response pathways. These include the two main DNA damage signaling pathways, initiated by the ATM and ATR checkpoint kinases, and the DNA double-strand break repair pathways involving homology-directed repair (HDR) and non-homologous end joining (NHEJ). Shelterin also protects telomeres from inappropriate resection by nucleases. Shelterin is compartmentalized such that different subunits repress distinct DNA damage response pathways.

de Lange’s group aims to determine the mechanism by which each shelterin subunit inhibits its designated pathway. A major mechanistic insight came from the identification of the t-loop structure of telomeres in which the single-stranded overhang is inserted in the double-stranded repeat array of the telomere, thereby hiding the telomere end from the DNA damage response. This structure is formed by the TRF2 component of shelterin. Since TRF2 is responsible for the repression of the ATM kinase pathway and non-homologous end joining, it is likely that the t-loop structure is critical to prevent these two pathways from acting inappropriately on chromosome ends. In addition, the lab showed how POT1, the single-stranded DNA (ss-DNA) binding protein in shelterin, prevents ATR kinase activation by masking the ss-DNA and preventing the ss-DNA sensor RPA from activating ATR.

A second focus of the lab is to understand how telomere dysfunction contributes to genome instability in cancer. When telomeres shorten beyond a critical length during tumorigenesis, they become a substrate for non-homologous end joining and form dicentric chromosomes. The lab modeled this so-called telomere crisis in vitro and showed that dicentric chromosomes can cause chromothripsis and kataegis, two extreme forms of mutational alteration observed in cancer.

A third area of interest is to understand how cells repair double-strand breaks. The team is particularly interested in the role of 53BP1, which is critical to the treatment of cancers deficient in the repair protein BRCA1. De Lange’s group recently showed that 53BP1 prevents the formation of long regions of ss-DNA through the use of a fill-in complex composed of the trimeric CST (CTC1/STN1/TEN1), polymerase α, and primase. They found that shelterin recruits CST/polα/primase to telomeres to mitigate over-resection and prevent excessive telomere shortening. Given its critical role at double-strand breaks and telomeres, CST/polα/primase is a major focus of the lab’s current studies.