Week 5: Chromosome Segregation

Question 1

Aneuploidy

Answer 1

1. Errors in chromosome transmission and other mitotic processes
2. It is the leading cause of age related infertility in developed world

Question 2

Sister chromatid cohesion

Answer 2

1. Cohesion is mediated by COHESIN complex in S (replication) phase: cohesion starts forming as soon as DNA is replicated to keep sister chromatids together to Ensure faithful genome transmission
2. In the metaphase-anaphase transition, cohesin needs to be destroyed via separase

Question 3

Cohesin complex

Answer 3

1. As a SMC monomer: the nucleotide binding domain folds on itself
2. The folded monomer can then become a SMC heterodimer and associate with ATP to bring the two NBD heads together
3. Cohesin complex is formed: Smc1/3 associate, Mcd1 (closes the loop), Scc3 (HEAT repeat subunits: protein-protein interactions), Pds5/Wpl1 (accessory units/regulatory)

Question 4

How does cohesion actually tether sister chromatids together

Answer 4

1. Single-ring model: ring model: 1 cohesin complex where both sister chromatids pass through
2. Oligomeric models: snap model versus bracelet model
   2a. Multiple cohesins assembled in different ways each complex allows for the passage of 1 sister chromatid

Question 5

Cell cycle dependant regulation of cohesion function

Answer 5

1. G1 phases loading of Scc2/4 which relies on ATP onto chromatid
   1a. Cohesin is very unstable here, it falls off/on again a lot (due to wpl1)
2. S phase: establishment: acetyltransferase Eco1 acetylates smc3 complexes to promote stable association of cohesin complex
3. G2/M phase: maintenance of the complex
4. Anaphase: dissolution (separase cleaves mcd1 to break cohesin apart)
5. Deacetylase Hos1 of smc3: repeat cycle

Question 6

Two step Removal of chromatin bound cohesin

Answer 6

1. Prophase removal: activation of mitotic kinases promote phosphorylation of Scc3 and sororin: cohesin falls off of DNA
   1a. To create space for DNA condensation at the ends (still maintained at centromere)
   1b. SGO1/PP2A doesn’t allow middle cohesin to fall off: keeps sororin in dephosphorylated state
2. Anaphase dissolution via separase
   2a. Separase held inactive via securin (phosphorylated)
   2b. Cdc20 activates APC (ubiquitin complex)
   2c. Securin destruction, separase inactive still (still phosphorylated)
   2d. Cyclin destruction: separase dephopshorylation =separase active
   2e. Via tension put on cohesion from separase, the sister chromatids are separated

Question 7

Model for the role of sororin

Answer 7

1. Telo/G1: Wapl attached =cohesin unstable
2. smc3 acetylation via Eco1 /DNA replication
3. S/G2: sororin binds to complex (with wapl)=stable cohesin
4. M phase: sororin gets phosphorylated via mitotic kinases; unstable cohesin