Cell Cycle

Question 1

name the different phases of the cell cycle

Answer 1

G1 or preparatory phase, longest phase

S phase, where DNA replication happens

G2 phase, where the cell is preparing for mitosis, checking for the right order

M phase - mitosis

Cytokinesis, cells split into two

Question 2

endoreduplication

Answer 2

cells with more than 2n copies of DNA

cells go through cell cycle stopping before mitosis

replication without splitting over and over again

Question 3

interphase

Answer 3

the time when the cell grows and replicates its DNA, divded into G1, S, and G2

Question 4

cyclin-dependent kinases (Cdks)

Answer 4

family of 11 related protein kinases, crucial for cell cycle progression and other activities

binds to cyclins, and Cdk-cyclins only have partial kinase activity

phosphorylation of specific amino acids on the Cdks can either activate or inhibit the kinase

Question 5

cyclins

Answer 5

bind to Cdks, at least 16 differeny cyclins, have varying levels during the cell cycle to dictate what happens at different points in time during the cell cycle

Question 6

four mechanisms that regulate Cdk activity

Answer 6

1. Association with cyclins
2. activating phosphorylation of threonine around position 160
3. inhibitory phosphrylation of threonine 14 and 15
4. Association with Cdk inhibitors (CKIs)

Question 7

CKI

Answer 7

cyclin-dependnt kinase inhibitor, along with inhibitor of Cdk4 (INK4 families bind to and activate the Cdk-cyclin complexes

some members of the CKI family also can act as positive cofactors for Cdk-cyclin assembly and activation

Question 8

Describe the four classes of cyclins that affect Cdk activity throughout the cell cycle.

Answer 8

Cyclin D synthesis beings in G1 and stays relatively constant until it is degraded and disappears through mitosis

Cyclin E is the G1/S cyclin, rises at the end of G1 and rapidly decreases at the beginning of S phase

Cyclin A is important for S phase and transition through G2

Cyclin B increases throughout G2 and then drops during mitosis after it peaks

Question 9

cyclical proteolysis of CKIs

Answer 9

SCF phosphorylates CKI and makes it a target for E1 and E2 ubiquitin ligase, which targets the CKI for degradation

Question 10

cyclical proteolysis of cyclins

Answer 10

done by APC after an activating subunit Cdc 20

ubiquitinylates cyclin/Cdk complex

APC = Anaphase promoting complex

M-Cdk activates APC, negative feedback loop

Question 11

three major cellc ycle checkpoints

Answer 11

G1/S, G2/M, and M/cytokinesis

Question 12

cell growth signals

Answer 12

GSK3beta and Ras

GSK3beta inhibits formation of Cyclin D1/Cdk4, Cyclin D1/Cdk6, and Cyclin E/Cdk2

Ras promotes Cyclin D1/Cdk4 and Cyclin D1/Cdk6

Question 13

TGFbeta

Answer 13

binds to a surface receptor serine-threonine kinase

signaling cascade promotes Smad3 and Smad4, which indirectly inhibits cdc25A and subsequently Cyclin D1/CDK4

Smad3/4 also indirectly inhibits p15 thorugh 19

Question 14

differentiation signals

Answer 14

p15 through 19, which inhibit Cyclin D1/Dck4 formation

Question 15

cell-cell-ECM contacts

Answer 15

activate GSK3beta and RhoA

GSK3beta inhibits beta-catenin/TCF, which indirectly activates Cyclin D1/Cdk6/4

RhoA indirectly inhibitis p21 and p27, which inhibit Cyclin D1/Cdk6/4 as well as Cyclin E/Cdk2

Question 16

DNA damage

Answer 16

activates ATM, which activates p53, which indirectly activates p21 and p27

Question 17

p16

Answer 17

indirectly inhibits Cyclin E/Cdk2

Question 18

retinoplastoma (Rb)

Answer 18

a protein that binds to transcription factor of E2F

can be mildly phosphrorylated by Cyclin D/Cdk4/6

hyperphosphorylated by cyclin E/Cdk2

Question 19

E2F

Answer 19

transcription factor regulated by Rb, when bound to Rb, recruits histone deacetylases to chromatin

when not bound to Rb, activates transcription of several hundred genes important for DNA synthesis and cell cycle progression

E2F is one of the genes activated, so there is a positive feedback loop

cyclin E, Cdk2, cyclin A, and other DNA replication factors are also activated

Question 20

CIP/KIP and INK4

Answer 20

two families of cyclin/Cdk inhibitors that help regulate cell cycle checkpoints

Question 21

Describe the process of Rb phosphorylation that leads to the activation of DNA replication

Answer 21

p27 helps promote the formation of Cyclin D/Cdk4 complexes, which gets transported to the nucleus

Cyclin D/Cdk4 mildly phosphorylates Rb, which allows the build up of cyclinE/Cdk2 through E2F release, can also soak up free-floating p27 in the nucleus

p27 in the nucleus initially inhibits Cyclin E/Cdk2 complexes, but as more Cyclin E/Cdk2 are formed and more Cyclin D/Cdk4 enters the nucleus, p27 gets phosphorylated and degraded

free Cyclin E/Cdk2 buildup can then hyperphosphorylate Rb and launch the cell into S phase

Question 22

Descrive the two positive feedback loops related to Cyclin E/Cdk2 formation

Answer 22

CKI is both phosphorylated and degraded as well as sequested onto Cyclin D/Cdk4 complexes

Question 23

myoD

Answer 23

a transcription factor that is the master regulator of muscle development, activates the transcription of p21, which inhibits several Cdk-cyclins

p21 also binds to the DNA replication factor PCNA, blocking the DNA replication

Question 24

contact inhibition

Answer 24

a process in cells that become growded, where Cdk inhibitor p27 is upregulated in cells that are touching neighboring cells

Question 25

control of DNA replication by S-phase cyclins

Answer 25

to ensure DNA replicatino only happens once per cycle, Cdc6 and Cdt1 bind to the origin recognition complex (ORC) MCM is able to assemble in the presence of Cdc6 cyclin complexes for the S-phase promoting factor (SPF) a build-up of Cyclin B/Cdk1 and Cyclin E/Cdk2 during phase leads to phosphorylation of Cdc6, leading to its degradation the assembled MCM complexes drive replication, but the ORCs are phosphorylated by the Cyclin/Cdk complxes and can no longer bind Cdc6/Cdt1 until the cycle is completed

Question 26

geminin

Answer 26

prevents Cdc6/Cdt1 from loading Mcm proteins, accumulates in S phase

Question 27

replication origin clusters

Answer 27

all clusters on the same chromosome fire at about the same time about 1000 of these clusters in human cells can be divided into "early" or "late" replicating origins R-bands are gene-rich and early replicating G-bands are gene poor and late-replicating later replicating DNA is concentrated around nucleoli and near the nucelar periphery where heterochromatin is abundant

Question 28

histone genes

Answer 28

transcription rises dramatically during S phase processing increases about 10 fold histone mRNAs are not polyadenylated, increased staability in cytoplasm during S phase stability decreases 40-fold in G2

Question 29

centrosome duplication

Answer 29

happens in S phase in preparation for the next mitosis

Question 30

cyclin E substrates

Answer 30

initiation of transcription from histone gene clusters initated by Cyclin E/Cdk4 also regulates centrosome replication Cyclin E/Cdk2 also phosphorylates NPM/B23, which releases it from the centrosome

Question 31

cyclin H

Answer 31

phosphorylates the cyclin D1/Cdk/pRB complex and is necessary for full cyclin D1 activity

Question 32

Describe the activities of the regulatory network that results from DNA damage.

Answer 32

ATM and ATR are the major sensing kinases that lead to phosphorylation of downstream factors, which lead to control of the cell cycle when DNA damage is detected

Question 33

How is mitosis suppressed until DNA replication is completed?

Answer 33

ATR is associated with the replisome, and it actively phosphorylates CHK1, which then phosphorylates CDC25A CDC25A gets degraded when phosphorylated by SCF, preventing the activation (dephosphorylation) of the Cyclin/Cdk2 complex

Question 34

Describe how the HPV oncoproteins deregulate the cell cycle checkpoints

Answer 34

E7 binds to Rb and related E2F suppression proteins to prevent Rb control of the G1/S checkpoint E6 binds p53 and targets it for degradation, which prevents the activation of p21, which workds to inhibit Cyclin E/A/B - Cdk2/1 complexes

Question 35

Describe how cells enter replicative senescence and what happens when telomerase becomes involved at various points of the cell's replicative lifespan.

Answer 35

replicative senescence after 50-70 divisions crisis after 80 divisions if checkpoints are lost, then telomeric crisis and death if telomerase is activated before replicative senescence, cells become immortal if cells are undergoing crisis and then telomerase is activated, they will become immortal with many genetic defects, often leading to cancer