The columnar structure of human telomeric chromatin suggests mechanisms for telomere maintenance

Abstract

Telomeres, the ends of eukaryotic chromosomes, play pivotal roles in ageing and cancer and are targets of DNA damage and response. However, little is known about the structure and organization of telomeric chromatin at the molecular level. We used electron microscopy and single-molecule magnetic tweezers to characterize well-defined telomeric chromatin fibers of kilobasepair length. The cryo-EM structure of the compact telomeric tetranucleosome revealed a novel columnar folding, unusually short nucleosome repeat length of ∼132bp and the role of the histone N-terminal tails in stabilizing this structure. This is the first near-high resolution structure of chromatin with a native DNA sequence. The columnar structure exposes the DNA, making them susceptible to DNA damage. The telomeric tetranucleosome also exists in an alternative well-defined state, with one nucleosome open, accessible to protein factors. This suggests that protein factors, which plays a role in maintaining telomeres, can bind to telomeric chromatin in its compact heterochromatic form. The features of the telomeric chromatin structure reveals important insights of significant relevance for telomere function in vivo that provides information on mechanisms of nucleosome recognition by chromatin factors

Telomeres and Their Neighbors

“…In 2001, Fajkus and Trifonov [ 270 ] proposed telomeric nucleosomes are packed in a variant, columnar chromatin structure. Recently, the formation of this structure was confirmed experimentally using cryoelectron microscopy [ 271 ]. The ends of telomeres associate with a more diverse set of proteins depending on organism that maintain a 3′ single-stranded overhang (aka G-overhang), recruiting enzymes to lengthen the 3′ strand and shorten the 5′ strand which induce and stabilize t-loop formation (reviewed in [ 9 , 272 ]).…”