Diversity in requirement of genetic and epigenetic factors for centromere function in fungi

Abstract

A centromere is a chromosomal region on which several proteins assemble to form the kinetochore. The centromere-kinetochore complex helps in the attachment of chromosomes to spindle microtubules to mediate segregation of chromosomes to daughter cells during mitosis and meiosis. In several budding yeast species, the centromere forms in a DNA sequence-dependent manner, whereas in most other fungi, factors other than the DNA sequence also determine the centromere location, as centromeres were able to form on nonnative sequences (neocentromeres) when native centromeres were deleted in engineered strains. Thus, in the absence of a common DNA sequence, the cues that have facilitated centromere formation on a specific DNA sequence for millions of years remain a mystery. Kinetochore formation is facilitated by binding of a centromere-specific histone protein member of the centromeric protein A (CENP-A) family that replaces a canonical histone H3 to form a specialized centromeric chromatin structure. However, the process of kinetochore formation on the rapidly evolving and seemingly diverse centromere DNAs in different fungal species is largely unknown. More interestingly, studies in various yeasts suggest that the factors required for de novo centromere formation (establishment) may be different from those required for maintenance (propagation) of an already established centromere. Apart from the DNA sequence and CENP-A, many other factors, such as posttranslational modification (PTM) of histones at centric and pericentric chromatin, RNA interference, and DNA methylation, are also involved in centromere formation, albeit in a species-specific manner. In this review, we discuss how several genetic and epigenetic factors influence the evolution of structure and function of centromeres in fungal species.

Fig. 1.

Centromeres are highly diverse in fungi. (A) Organization of DNA elements and associated chromatin in point (S. cerevisiae), small regional (C. albicans), and large regional (S. pombe and N. crassa) centromeres. *, ORF-free regions containing CENP-A-rich centromeres are 4 to 18 kb long. (B) Domains of canonical histone H3 and centromere-specific histone H3 of the CENP-A family. While both the N-terminal domain and C-terminal histone fold domain (HFD) in histone H3 are highly invariant, the former is highly variable among centromeric histone H3 (CENP-A) proteins. Even the HFD is more variable in CenH3 than in histone H3. The α-helices (α-N, α-1, α-2, and α-3), loops (L1 and L2), and CENP-A targeting domain (CATD) present in the L1-α2 region of CenH3 are shown.

Fig. 2.

Centromere “establishment” versus “propagation”: epigenetic control of centromere function (see text for details). WT, wild type; Loss freq., loss frequency.