The regulation of chromosome segregation via centromere loops

Abstract

Biophysical studies of the yeast centromere have shown that the organization of the centromeric chromatin plays a crucial role in maintaining proper tension between sister kinetochores during mitosis. While centromeric chromatin has traditionally been considered a simple spring, recent work reveals the centromere as a multifaceted, tunable shock absorber. Centromeres can differ from other regions of the genome in their heterochromatin state, supercoiling state, and enrichment of structural maintenance of chromosomes (SMC) protein complexes. Each of these differences can be utilized to alter the effective stiffness of centromeric chromatin. In budding yeast, the SMC protein complexes condensin and cohesin stiffen chromatin by forming and cross-linking chromatin loops, respectively, into a fibrous structure resembling a bottlebrush. The high density of the loops compacts chromatin while spatially isolating the tension from spindle pulling forces to a subset of the chromatin. Paradoxically, the molecular crowding of chromatin via cohesin and condensin also causes an outward/poleward force. The structure allows the centromere to act as a shock absorber that buffers the variable forces generated by dynamic spindle microtubules. Based on the distribution of SMCs from bacteria to human and the conserved distance between sister kinetochores in a wide variety of organisms (0.4 to 1 micron), we propose that the bottlebrush mechanism is the foundational principle for centromere function in eukaryotes.

NCAPH is negatively associated with Mcl‑1 in non‑small cell lung cancer

“…NCAPH is one of the members of the barr gene family and is located on chromosome 2q11.2 ( 39 ). A previous study has indicated that NCAPH is one of the essential factors for maintaining cell survival and is indispensable in mitotic chromosome cohesion and separation ( 40 ). Mcl-1 is homologous to Bcl-2 and possesses an anti-apoptotic effect in regulating cell survival ( 41 ).…”

Common Features of the Pericentromere and Nucleolus

“…DNA Loops Are Enriched in the Pericentromere and Nucleolus While DNA looping was first observed in 1906 in salamander eggs [8], DNA loops have since been thoroughly documented in a number of different species [9]. These loops can potentially regulate many functions within the cell, including transcription, recombination, and replication [6,10]. Though DNA loops are present in various locations throughout the genome, both the pericentromere and the nucleolus are regions of high loop density that are controlled by unique protein interactors.…”

“…In the pericentromere, highly looped DNA has been found in budding yeast (Saccharomyces cerevisiae) [11,12] as well as in multicellular organisms such as Xenopus laevis [13] and chicken cells [14]. In budding yeast, centromeres from the 16 chromosomes cluster together into a disc approximately 50 nm by 250 nm, which connects to the microtubule plus-ends (for review, see [6]). From here, the pericentric region consists of protruding intramolecular centromere loops, or C-loops, that are formed by loss of sister chromatid cohesion, with radial sub-loops forming off of each C-loop [11,12,15,16] ( Figure 1A).…”

“…In yeast lacking Sir2, condensin becomes more radially displaced, distal to the spindle and perpendicular to the spindle axis, and can appear as a bilobed distribution similar to pericentric cohesin [17]. Condensin also has a role in positive supercoiling of DNA in both Xenopus [57] and budding yeast [58], which may promote proper segregation as positively supercoiled DNA is more resistant to pulling forces [6,59]. Meanwhile, in rDNA, FISH studies in budding yeast indicate that condensin is necessary for rDNA looping [43][44][45][46].…”

“…However, in regional centromeres, which are enriched in heterochromatic alpha satellite repeats, there are multiple sites of microtubule attachment. Despite these differences, the interkinetochore distance is conserved among eukaryotes [6], suggesting an important conservation of centromere mechanics.…”