Guarding the genome: Maintaining epigenetically defined human centromeres through error correction

The centromere is a central genetic element responsible for accurate chromosome segregation during cell division. Functional centromeres are specified epigenetically through the stable acquisition of CENP-A, a histone H3 variant found exclusively in nucleosomes at all active centromeres. Using genome-wide approaches, we recently discovered CENP-A binding sites within the megabase-long, repetitive α-satellite DNAs at each centromere. We find that CENP-A is assembled in early G1 into nucleosomes within each centromere and onto ectopically 11,390 transcriptionally active sites on the chromosome arms. DNA replication is demonstrated to remove ectopically loaded, non-centromeric CENP-A. In contrast, tethering of centromeric CENP-A to the sites of DNA replication through the constitutive centromere associated network (CCAN) is shown to enable precise reloading of centromere-bound CENP-A onto the same DNA sequences as in its initial prereplication loading. Thus, DNA replication serves as an error correction mechanism that restricts CENP-A to centromeres by removing it from the ectopic sites of deposition at the chromosome arms, while maintaining the positions of centromere-bound CENP-A with high precision throughout DNA replication. This error correction mechanism explains how centromere identity is epigenetically maintained and restricted to one position on the chromosome, thereby suppressing genome instability and ensuring long-term faithful chromosome inheritance.