CENP-B-mediated DNA loops regulate activity and stability of human centromeres

• DOI: 10.1016/j.molcel.2022.02.032
• Publication Date: 2022-03-22T14:28:24Z
• Authors: Florian Chardon; Aleksandre Japaridze; Hannes Witt; Leonid Velikovsky; Camellia Chakraborty; Therese Wilhelm; Marie Dumont; Wayne Yang; Carlos Kikuti; Stephane Gangnard; Anne-Sophie Mace; Gijs Wuite; Cees Dekker; Daniele Fachinetti
• Keywords: 0301 basic medicine; chromosomes; secondary structures; DNA compaction; optical tweezers; Chromosomal Proteins, Non-Histone; Centromere; 612; DNA; Autoantigens; Chromatin; DNA topology; 03 medical and health sciences; centromere; Humans; DNA breaks; AFM microscopy; CENP; genome stability; Centromere Protein A

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.