L6 cohesion complex

Flashcards covering key terms and concepts related to the cohesin complex and its roles in chromosome biology and cancer.

Cohesin complex

A protein complex that holds sister chromatids together and organizes chromatin during cell division.

heterodimer of SMC proteins (1 and 3) and non-SMC subunits (ATP, RAD21, SCC1/2)

at what mitotic phase is cohesin loaded onto chromosomes

G1 phase before DNA replication

cohesin complex functions in mitosis

• sister chromatid cohesion (at centromeres)

• holding together sister centrioles

cohesin complex functions in meiosis

• pairing of homologous chromosomes

• assembly of axes of synaptonemal complex

• coordination of sister kinetochores during first meiotic division

cohesin complex functions in interphase

• sister chromatids cohesion (entire chromatin)

• repair of DNA breaks

• assembly of DNA replication factories during S phase

• regulation of transcription

• organisation of chromatin loops and TADs

cohesin complex functions in centrosomes

maintains paired centrioles

centrosome number is tightly controlled

SMC proteins

Structural Maintenance of Chromosomes proteins that form part of the cohesin complex, specifically SMC1 and SMC3.

phases for cohesin removal from chromosomes during mitosis

1. removal from chromosomal arms - mitotic kinases

2. removal from centromeres - separase

Aneuploidy

An abnormal number of chromosomes in a cell, commonly found in cancer cells.

Spindle assembly checkpoint (SAC)

A surveillance mechanism that ensures proper attachment of kinetochores to microtubules before proceeding with anaphase.

Mps1

responsible for sensing attachment of MTs to KTs

SAC activity gives cells more time to establish proper MT-KT connections

without this extra time, cells may proceed to anaphase without MT-KT attachment

why is aurora B considered part of SAC

aurora B phosphorylates Mps1 and regulates tension across sister chromatids, ensuring proper checkpoint signaling.

MPS1 can distinguish when NDC80 is bound to MT or not

what is the dual role of Aurora B?

Error correction system: Low tension → phosphorylation of NDC80 → detachment of kinetochores → unattached KT recognised by SAC

And SAC activity: MPS1 phosphorylated by aurora B to sense proper microtubule attachment

Mitotic Checkpoint Complex (MCC)

kinetochores that are improperly attached/ under insufficient tension produce MCC, A “STOP’ signal complex of SAC proteins (BubR1, Bub3, Mad2, Cdc20)

binds to APC/C to delay anaphase until all kinetochores are properly attached and aligned on metaphase plate

satisfaction of checkpoint leads to degredation of cyclin B and securin

Separase

An enzyme that is responsible for cleaving cohesin, allowing sister chromatids to separate during anaphase.

how is separase activity controlled?

activation of separase is triggered by proteasome pathway

APC/C (anaphase-promoting complex/cyclosome)

is a ubiquitin ligase that triggers the degradation of cyclin and other proteins, thereby activating separase.

controlled by SAC

proteasome pathway

ubiquitylation of targeted proteins by APC/C → degradation of the regulatory proteins

regulation checkpoint from one stage of mitosis to another

pre-requisite for metaphase to anaphase transition

• inactivation of CDK1

• activation of separase

both triggered by proteasome pathway

what happens when APCC is activated during metaphase

• degradation of securin → activates separase → chromosome segregation (separase cuts cohesin at centromere)

• degrade cyclin B (activator of CDK1) → inactivates CDK1 → mitotic exit

Cohesion-dependent functions

Functions of cohesin that rely on its ability to hold sister chromatids together.

Cohesion-independent functions

Functions of cohesin that do not involve sister chromatid cohesion but are related to chromatin organization and gene regulation.

Mad2

A component of the Mitotic Checkpoint Complex; it binds to unattached kinetochores to signal a delay in anaphase.

Cohesin cycle

1. non-cohesive cohesin loaded onto DNA after G1 phase with the help of Scc2 cohesin loading factor

• there is no sister chromatid in G1 phase

1. Eco1 acetylates cohesin during S phase to create cohesive cohesin (can hold sister chromatids together)

2. cohesion of sister chromatids is established in G2 phase

3. cohesin is removed completely from chromatin during mitosis

cohesive vs non-cohesive cohesin

non-cohesive cohesin doesn’t bind sister chromatids together, bound to only 1 sister chromatid

how is cohesin removed during mitosis?

2 waves

prophase (mitotic kinase) pathway

• Plk1 + Wapl kinases phosphorylate cohesins that are in the arms of chromosomes → prevents cohesin binding to DNA

• shugoshin protein and Protein Phosphatase 2A protect centromeric cohesin - not removed

separase pathway

• cohesin in the centromere - holds two sister chromatids together

• enzymatic pathway which degrades centromeric cohesin → anaphase can occur

Regulatory proteins

Proteins that are involved in controlling the activity of other proteins, crucial for cell cycle transition.

how does SAC perform its function

• inhibition of the removal of centromeric cohesion

• inactivation of mitotic kinase CDK1

centrosome duplication cycle

1. separase disengages centrioles by cutting cohesin (centrioles are held together by cohesin)

2. centrioles undergo duplication to create daughter centrioles

3. daughter centrioles undergo mitosis