Frodos found: Behold the CENP-a "Ring" bearers

Abstract

CENP-A is a histone H3-like protein specific to centromeres that is essential for kinetochore formation and accurate chromosome segregation in eukaryotes. Recent studies (Dunleavy et al., 2009; Foltz et al., 2009; Perpelescu et al., 2009; Pidoux et al., 2009; Williams et al., 2009) analyze CENP-A binding proteins required for the recruitment of CENP-A to centromeres in humans and in fission yeast, bringing us closer to understanding how centromere identity is faithfully propagated.

Figure 1. CENP-A Recruitment to S. pombe and Human Centromeres

(A) In Schizosaccharomyces pombe, centromeric DNA is replicated and existing CENP-A^Cnp1 is diluted by nucleosome segregation to sister chromatids during S phase. Recruitment of new CENP-A^Cnp1 occurs during both S and G2 phases (red dotted line/double arrowheads). The Sim3/NASP histone chaperone interacts with free CENP-A^Cnp1 and delivers it to the centromere, where it is received by SpScm3 and assembled into nucleosomes by unknown factors and mechanisms. Nucleosome gaps could be filled or H3 nucleosomes could be replaced. SpScm3 is shown as a dimer interacting directly with Mis18. SpScm3 recruitment at centromeres requires the Sim4/Mis6 and Mis16/Mis18 complexes. Mis16/Mis18 and SpScm3 are removed from centromeres during mitosis and reassociate starting in late anaphase. (B) In humans, centromere replication during S phase creates CENP-A nucleosome “gaps” (with or without H3 nucleosome deposition) that are replenished only when new CENP-A assembly occurs in the following late mitosis through G1 phases (red dotted line/double arrowheads). Interactions between chromatin-free CENP-A and HJURP, which ensures the stability of free CENP-A, occur throughout the cell cycle but levels of both proteins increase closer to mitosis. Stabilization of HJURP is mediated by RbAp46/48 through an unknown mechanism. In telophase, the human Mis18 complex is recruited to centromeres, followed by HJURP. The ATP-dependent remodeling and spacing factor (RSF) complex is recruited to the centromere in mid-G1 phase and interacts with CENP-A nucleosomes. It could mediate the assembly of CENP-A into chromatin, or stabilize already assembled CENP-A nucleosomes by promoting incorporation of H2A/H2B or H2A variants or regulating nucleosome phasing. The proteins responsible for HJURP, RSF, and Mis18 recruitment to centromeres are not known, nor is the function of Npm1 in centromere assembly.