How telomeres solve the chromosome end‐protection problem

Abstract

Chromosome ends can activate the DNA damage response (DDR) signaling pathways and become substrates for Double‐strand Break (DSB) repair. Telomeres solve this end‐protection problem by repressing all forms of DDR signaling and DSB repair. The telomeric DNA, maintained by telomerase, binds a six‐subunit protein complex, termed shelterin, that protects chromosome ends. Shelterin binds to the double‐stranded (ds) telomeric DNA through two subunits, TRF1 and TRF2. These proteins recruit a single‐stranded (ss) telomeric DNA binding factor, POT1, which binds to the ss telomeric repeats present at all chromosome ends. POT1 is linked to TRF1 and TRF2 via interactions involving TPP1 and TIN2. A sixth component, Rap1, interacts with TRF2. Conditional knockout experiments in mouse embryonic fibroblasts (MEFs) have revealed the mechanism by which this simple protein complex prevents activation of the ATM and ATR DNA damage signaling pathways, represses 5′ end resection, and prevents non‐homologous end joining (NHEJ) and homology directed repair (HDR) at telomeres. Shelterin is compartmentalized such that TRF2 represses ATM signaling and NHEJ, whereas ATR signaling is repressed by POT1. The mechanism by which TRF2 represses ATM signaling and NHEJ involves the remodeling of telomeres into the t‐loop structure, which essentially hides the chromosome end. POT1 represses ATR signaling by preventing the ssDNA sensor in the ATR pathway, RPA, from binding to telomeres. Progress on the mechanistic aspects of shelterin mediated chromosome end protection will be presented.Support or Funding InformationDr. de Lange is funded by awards from the NIH, American Cancer Society, the Breast Cancer Research Foundation, and the STARR Cancer ConsortiumThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.