2009年8月25日

Clearing the way for mitosis: is cohesin a target?

Nature Reviews Molecular Cell Biology 10, 489-496 (July 2009)
Clearing the way for mitosis: is cohesin a target?
By Mitsuhiro Yanagida

Box 1: Component of cohesin complex and two hypothetical models
a. Componet of cohesin complex
•two structural maintenance of chromosome (SMC) subunits, SMC1 and SMC3,
•contain large coiled-coil domains
•have ATPase activities
•two non-SMC subunits, RAD21 and SCC3
b. Ring-like cohesion comlex model
c. Other model proposed by Koshland et. al.

Figure 1 | control of chromosomal dynamics in mitosis.
Interphase: sister chromatids are held
together by cohesin
Prophase:
•Activation of
•cyclin-dependent kinase 1 (CDK1),
•Polo-like kinase 1 (PLK1),
•Aurora B
•the spindle assembly check point (SAC)
•chromosome condensation
•nuclear envelope breakdown.
Prometaphase: mitotic checkpoint complex (MCC) :proposed to inhibit the ability of cell division cycle 20 (CDC20) to activate the e3 ubiquitin ligase anaphase promoting complex or cyclosome (APC/C).
Metaphase: In metaphase, the chromosomes and kinetochores align in the middle of the mitotic spindle,
Anaphase: cyclin B (an activator of CDK1) and securin (the inhibitor of separase) are ubiquitylated by the APC/C and degraded by the 26S proteasome.
Telophase: the chromosomes in the daughter nuclei decondense.

Figure 2 | DNA topological constraints under continuous TOP2 action.
a. Three known topological natures of DNA
supercoiling, knotting and catenation.
Eukaryotic DNA topoisomerase II (TOP2): an ATP-dependent enzyme, catalyses the conversions
b. Two kinds of supercoiling occur in chromosomal DNA.
c. When transcription proceeds in the direction indicated by the arrow, negative supercoils are formed behind, but positive supercoils are made in front of, the transcription machinery if the DNA ends are not freely rotated.
d. In metaphase and anaphase, the chromosome arms might be topologically separated in the presence of TOP2, but become catenated in the absence of TOP2. TOP2 continuously acts on the chromosomes during mitosis, avoiding decondensation and catenation between DNA strands.
e. Polo-like kinase 1 (PLK1)-interacting checkpoint helicase (PICH):
a member of the SNF2 family of ATP-dependent DNA helicases.
decorates the centromeric DNA threads during anaphase
TOP2: required for the resolution of the PICH-decorated threads in anaphase.

Figure 3 | Possible role of condensin in chromosome 'cleansing'.
a. The holocomplex of condensin contains
2 structural maintenance of chromosome (SMC) subunits, SMC2 and SMC4
3 non-SMC subunits condensin non-SMC defective (Cnd1), Cnd2 and Cnd3
b. The SMC heterodimer rapidly re-anneals single-stranded DNA (ssDNA)
c. Condensin might function in clearing mitotic chromosomes through SMC dimer-mediated DNA annealing to eliminate proteins and RNA transcripts that are bound to the unwound ssDNA.  Non-SMC subunits might have a negative, regulatory role.

Figure 4 | cohesin loading and 'cleansing' model for cohesin in mitosis.
a. G1 phaseにおいてcohesinはScc2によってloadingされ、Eco1によってアセチル化されてS phaseにはcohesive cohesinとなってDNA二本鎖を束ねる。
Early prophaseには、Plk1によってリン酸化されて、cohesive cohesinが減ってゆくが、これはPp2aに結合したSgoによって拮抗する。
MetaphaseにはSeparaseによるcohesinの解離が進行してAnaphaseにはすべてのcohesinが染色体から離れている。
Bではcohisin complexだけがpulling forceに拮抗するopposing forceの源と考えられているが、筆者は、cのようにcohisinはまだ明らかになっていないcmposit opposing forceの一つであって、cohesinが除去される過程においてすべてが解除されて初めてanaphaseにおける染色体の分離が実現すると考えている。