The dark side of centromeres: types, causes and consequences of structural abnormalities implicating centromeric DNA

Abstract

Centromeres are the chromosomal domains required to ensure faithful transmission of the genome during cell division. They have a central role in preventing aneuploidy, by orchestrating the assembly of several components required for chromosome separation. However, centromeres also adopt a complex structure that makes them susceptible to being sites of chromosome rearrangements. Therefore, preservation of centromere integrity is a difficult, but important task for the cell. In this review, we discuss how centromeres could potentially be a source of genome instability and how centromere aberrations and rearrangements are linked with human diseases such as cancer.

Fig. 1

Centromere breakage and human diseases. Representation of the genomic alterations deriving from centromere breaks such as aneuploidy, dicentric, and neocentromere chromosomes, Robertsonian translocations together with loss of methylation at (peri)centromere (typical of ICF syndrome), all known to contribute to human diseases

Fig. 2

Origins of centromeric breaks. Schematic of the possible causes that lead to chromosome breaks at centromere. a Segregation errors: merotelic attachment and k-fiber accumulation are the sources of lagging chromosome formation and centromere distortion in mitosis leading to micronuclei and centromere breaks. b DNA topology: the complex DNA topology enriched in catenanes is normally resolved by topoisomerases prior to completion of sister chromatid separation. Resolution of UFBs is also crucial for maintenance of genome integrity in which a fraction of those results in 53BP1 nuclear bodies (NB) that are repaired in the next cell cycle. Alterations in the centromere decatenation pathway can lead to anaphase bridges and DNA breaks. c, d DNA replication and recombination: due to its highly repetitive sequences a non-canonical pathway of DNA damage and homologous recombination proteins is implicated in the correct completion of centromere replication in order to avoid formation of anaphase bridges, unscheduled recombination and, consequently, segregation errors and breaks

Fig. 3

Neocentromeres and chromosome instability. A neocentromere forms at chromosomal locations different from the centromere’s original position. The possible causes of neocentromere formation, depicted here, span from epigenetic inactivation, centromere erosion, CENP-A mislocalization to rescue of acentric DNA fragments following chromosome rearrangements. Neocentromeres display, however, a low degree of heterochromatin, loss and reduction of centromeric proteins (CENPs), mislocalization of Aurora B and alteration of DNA replication that cause a decrease in chromosome segregation fidelity

Fig. 4

Dicentric chromosomes and chromosome instability. Representation of the possible origins of dicentric chromosomes that arise from chromosome/telomere fusions or neocentromere formation in the presence of a functional original centromere. During anaphase onset, the dicentric chromosome that is attached by opposing mitotic spindle fibers is trapped, leading to anaphase and chromosome bridges and, consequently, DNA damage and chromosome instability. Centromere inactivation could restore faithful segregation by preventing incorrect spindle attachment