Processing of Alternative DNA Structures in the Human Telomere

摘要: Telomeres help maintain the overall genomic stability of an organism, and telomeric homeostasis is critical to navigating between aging cancer. Telomeric dysfunction implicated as a contributing factor in numerous aging-related diseases, such diabetes, impaired hematopoeisis, atherosclerosis. maintained by shelterin complex six proteins array telomere-associated that interact with central complex, Werner syndrome helicase/exonuclease protein (WRN) or p53. also have non-canonical DNA structures are towards their function, especially G-quadruplex (G4 DNA) Holliday Junctions. The former pseudoknots form on G-rich 3' single-stranded tail telomere may block replication lengthening, when exposed "open" conformation. We found protection telomeres 1 (POT1) competes destabilizes G4 physiologically realistic substrate, leading equilibrium population diminished coexisting POT1. While POT1 passive binder DNA, destabilizing effect bound pre-existing leads emergent, de facto cooperativity unfolding POT1.Holliday Junctions (HJ) "closed" conformation, which invades duplex creating displacement loop (D-loop) sequestering end chromosome from unwanted damage responses. D-loop homologous recombination intermediate, we demonstrate repeat binding 2 (TRF2) necessary protect HJ WRN helicase activity, has been thought branch migrate into target for Junction cleaving enzymes, causing sudden shortening. TRF2 protects cleavage due largely HJ-binding B-domain TRF2. In contrast, TRF2-mediated against depends both B domain telomeric-repeat Myb domain. therefore discovered overlapping but distinct role maintaining stability.Our work elucidated novel structural functional data modulation proteins. These us elucidate mechanisms underlying cellular animal models instability aging.