CENP-B-mediated DNA loops regulate activity and stability of human centromeres
Florian Chardon (PSL Research University)
Aleksandre Japaridze (TU Delft - BN/Cees Dekker Lab, Kavli institute of nanoscience Delft)
Hannes Witt (Vrije Universiteit Amsterdam)
Leonid Velikovsky (PSL Research University)
Camellia Chakraborty (PSL Research University)
Therese Wilhelm (PSL Research University)
Marie Dumont (PSL Research University)
Wayne Yang (Kavli institute of nanoscience Delft, TU Delft - BN/Cees Dekker Lab)
Cees Dekker (Kavli institute of nanoscience Delft, TU Delft - BN/Cees Dekker Lab)
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Abstract
Chromosome inheritance depends on centromeres, epigenetically specified regions of chromosomes. While conventional human centromeres are known to be built of long tandem DNA repeats, much of their architecture remains unknown. Using single-molecule techniques such as AFM, nanopores, and optical tweezers, we find that human centromeric DNA exhibits complex DNA folds such as local hairpins. Upon binding to a specific sequence within centromeric regions, the DNA-binding protein CENP-B compacts centromeres by forming pronounced DNA loops between the repeats, which favor inter-chromosomal centromere compaction and clustering. This DNA-loop-mediated organization of centromeric chromatin participates in maintaining centromere position and integrity upon microtubule pulling during mitosis. Our findings emphasize the importance of DNA topology in centromeric regulation and stability.