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

Cohesion

Answer 3

1. Mediated by the multi-subunit cohesion complex
   1a. As a SMC monomer: the nucleotide binding domain folds on itself
   1b. The folded monomer can then become a SMC heterodimer and associate with ATP to bring the two NBD heads together
   1c. 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

Is cohesion conserved throughout eukaryotes (delete)

Answer 4

1. Yes

Question 5

How does cohesion actually tether sister chromatids together

Answer 5

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 6

Cell cycle dependant regulation of cohesion function

Answer 6

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 7

Separase activation

Answer 7

1. Separase held inactive via securin (phosphorylated)
2. Cdc20 activates APC (ubiquitin complex)
3. Securin destruction, separase inactive still (still phosphorylated)
4. Cyclin destruction: separase dephopshorylation =separase active
5. Via tension put on cohesion from separase, the sister chromatids are separated

Question 8

Two step Removal of chromatin bound cohesin

Answer 8

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)
2. Anaphase dissolution via separase