Neocentromeres and epigenetically inherited features of centromeres

Abstract

Neocentromeres are ectopic sites where new functional kinetochores assemble and permit chromosome segregation. Neocentromeres usually form following genomic alterations that remove or disrupt centromere function. The ability to form neocentromeres is conserved in eukaryotes ranging from fungi to mammals. Neocentromeres that rescue chromosome fragments in cells with gross chromosomal rearrangements are found in several types of human cancers, and in patients with developmental disabilities. In this review, we discuss the importance of neocentromeres to human health and evaluate recently developed model systems to study neocentromere formation, maintenance, and function in chromosome segregation. Additionally, studies of neocentromeres provide insight into native centromeres; analysis of neocentromeres found in human clinical samples and induced in model organisms distinguishes features of centromeres that are dependent on centromere DNA from features that are epigenetically inherited together with the formation of a functional kinetochore.

Figure 1. Models to induce neocentromere formation

(A) D. melanogaster ectopic kinetochores can be induced by γ-irradiation or overproduction of CENP-A. Following, γ-irradiation, chromosome fragments were stabilized by neocentromeres if the fragment was adjacent to the native centromere. Following CENP-A overexpression, ectopic kinetochores assembled at the border of euchromatin and heterochromatin, resulting in dicentric chromosomes. (B) S. pombe neocentromeres can be induced by recombination-mediated deletion of the native centromere. All neocentromeres formed near subtelomeres. (C) C. albicans neocentromeres can be induced by replacing the native centromere with a selectable marker through by DNA transformation. Neocentromeres formed proximal to the native centromere or distal to the native centromeres on chromosome arms. Drawings not to scale.

Figure 2. Efficient DNA replication at fungal centromeres

(A) Centromeres are the earliest and most efficient origins on each C. albicans chromosome. The replication timing profile for chromosome in wild-type cells is indicated in blue. The position of CEN1 is indicated with a green line. (B) Centromere DNA in C. albicans and related species contains GC-skew, a replication-dependent strand-bias sequence pattern characteristic of constitutively active replication origins. Mean GC-skew (blue) and AT-skew (red) skew at the C. albicans centromere regions from all chromosomes are shown. (C) In S. pombe, CEN1 replicates earliest of all loci on chromosome 1. The centromere is indicated in green, while black, magenta, blue and red lines indicate data from different S. pombe replication timing microarray experiments (Feng et al., 2006, Heichinger et al., 2006, Mickle et al., 2007). (D) Neocentromere loci become the earliest, most efficient origins following kinetochore assembly, indicating that the replication pattern is determined by the presence of a function kinetochore. The native centromere (green line) is the earliest replicating region in wild-type cells (blue line), while the neocentromere locus approximately 170kb from the left telomere (black line) is the earliest replicating region in cells with this homozygous neocentromere (red line). Gray lines indicate a gap in data from the multiple repeat sequences in C. albicans on the right arm of chromosome 5. (E) Model for coordination of replication timing and maintenance of centromere specification. Adapted from (Koren et al., 2010).