cell cycle

purpose of G1?

growth and preparation for DNA synthesis

purpose of S phase?

DNA replication

G2 purpose?

organelle replication

what is G0?

cell exits cell cycle

how are the stages of mitosis defined?

by chromosome behaviour

2 main purposes of the cell cycle

faithful DNA duplication, accurate DNA segregation

what protein complexes are responsible for controlling cell cycle checkpoints?

cyclin-CDKs

what are the 3 main checkpoints?

G1/S (R point), G2/M, metaphase-to-anaphase transition

why are checkpoints important?

ensures key tasks (DNA replication/segregation) have been completed

which cyclin-CDK complexes are responsible for activating the G1/S checkpoint?

cyclin E-CKD2

how does cyclin D-CDK4/6 regulate cell cycle progression?

the complex will phosphorylate Rb but not enough to activate transcription factors E2F and DP

how does cyclin E-CDK2 regulate G1/S and aid cell cycle progression?

cyclin E-CDK2 will hyperphosphorylate Rb that will activate E2F and DP to transcribe genes for G1/S progression

which cyclin-CDK controls DNA damage checks during S phase?

cyclin A-CDK2

which cyclin-CDK complex is responsible for regulating the G2/M checkpoint?

cyclin B-CDK1

how is the p53 pathway initiated?

ATM or ATR kinases will be activated in response to different types of DNA damage: ATM for DSBs, ATR for other types of DNA damage. ATM will recognise DNA ends and chromatin, becoming active and phosphorylating p53. ATR forms a complex with ATRIP and will be recruited in the increased presence of replication protein A (RPA) ssDNA on replication forks or origins

what 3 outcomes may arise after DNA damage is identified?

cell cycle arrest, DNA repair, apoptosis

name a CDK inhibitor

p21

other than DNA damage response, what else is the p53 pathway responsible for?

regulation of CDK inhibitors

what type of radiation causes double-strand breaks (DSBs)?

ionising radiation

other than ATM and ATR, what other proteins activate p53?

checkpoint kinases (chk) 1 and 2

what does Cdc25a do to CDKs?

removes phosphate from CDKs, inhibiting their activity

what does Wee1 do?

adds an inhibitory phosphate to CDKs

what does GADD45 do?

stops cell growth and inhibits CDK1

what does the metaphase to anaphase transition depend on?

spindle assembly - unattached kinetochores will catalyse the formation of the mitotic checkpoint complex (BubR1, Bub3, Mad2, Cdc20). MCC will inhibit APC/C (anaphase promoting complex) and prevent mitosis from carrying on

how does Ras promote cell cycle progression?

Ras overexpression leads to the G1/S checkpoint being bypassed

what are the names of 2 CDK inhibitor families?

INK4, CIP/KIP

which genes for proteins involved in the cell cycle are classed as oncogenes?

cyclins, CDKs, E2F, Mdm2 (inhibits p53)

which proteins involved in the cell cycle are considered tumour suppressors?

RB, p53, p21, ATM/ATR, Chk1/2

what is Myc?

family of oncogenes that are deregulated in more than 50% of cancers, they form heterodimers with Max to stimulate transcription of genes involved in cell cycle such as cyclins, CDKs and CDKis

other than upregulating cyclin CDKs, how else does Myc promote cell cycle progression in cancer?

restricts activity of p21 and p27 (CDK inhibitors) and promotes DNA replication by inducing expression of genes such as origin recognition complex genes

what are the 3 types of Myc?

c-Myc (most common), N-Myc, L-Myc

how exactly does Myc suppress p21 activity?

Myc blocks its transcription by forming complexes with Miz-1 (and sometimes DNA methyltransferase 3a) to form a transcription repressor

other than targeting ORC (origin recognition genes), how does Myc promote DNA replication in a transcription-independent manner?

Myc interacts with the pre-replicative complex and localizes to origins of DNA replication where it initiates premature origin firing and increases origin density, leading to asymmetrical fork progression. this mechanism also explains how deregulated Myc generates DNA replication stress and DNA damage

why is it so difficult to use Myc as a therapeutic target?

it has an intrinsically disordered structure, lack of a suitable binding pocket for small molecule inhibitors, and its nuclear localization

what is OmoMyc and how does it work?

it is a small protein that blocks the complex formation between Myc and Max required for activating transcription. recently passed phase 1 clinical trial and shown to be successful in treating various solid tumours

what is APTO-253 and how does it work?

a compound that stabilizes a G4 (G-quadruplex) structure in the MYC promoter, decreasing MYC expression, inhibiting growth, and inducing apoptosis. APTO-253 has progressed to a phase I clinical trial for patients with relapsed/refractory acute myeloid leukemia or myelodysplastic syndrome and was shown to stabilise metastatic tumours