Cell cycle

ordered series of events tha lead to cell division and produciton of 2 daughter cells

G1 - DNA is preparing to divide, goes to S if DNA is intact and enough resources G0 - resting- none dividing phase, exits the cell cycle S - where the cell replicates DNA, goes to G2 if no errors in replication G2 - continued growth, prepare for division, needs to have intact DNA, all chromosomes and cell components to go to M M - where the cell divides

Cell division - cell makes identical daughter cells in response to molecular signals such as growth factors Differentiation - when cells stop dividing to specialize in structure and function. Some of them can’t re enter cell cycle Apoptosis- when cells die because they are old or unhealthy, if the cell genome has been damaged or for development

• When it receives a signal to differentiate • there is not enough nutrients to grow, or growth factors (called mitogens, signals to divide )

Neurons and muscle cells never re enter the cell cycle*

anueploidy/polyploidy - unequal chromosome sep Tumor formation - if turn off tumor supressor + turn on proto oncogenes

regulates proliferation, cell growth, found in intesting to maintain stem cell niche if it is defective the cell divide uncontrollably

S, also where DNA is checked for errors

CDK- most important cell cycle regulators, kinases. we don’t want them active allt eh time Activating CDK- cycling stimulates cell cycle, makes sure DNA is normal G1 - push cell cycle to S phase when growth factors cause cycling concentrations to rise and activate CDK S - CDK cyclin stimulate cell to reduplicate DNA Its activated when it binds to cyclin. CDK is present all the time, cyclin is not Kinases are proteins that phosphorylate The phosphate can activate or deactivate target .

CDK has T loop which blocks atp the cyclin A induces confromational change in CDK and moves the T loop slightly out of the way - makes it low activity sometimes it also requires cyclin acivated kinase to phosphorylate the t loop and make CDK even more active. Cdc25 - dephosphorylates other parts of CDK that are inhibitory

cyclin dependant kinase (CDK) - catalytic subunit - intrinsically inactive, due to t loop that naturally blocks atp pocket cyclin - regulates CDK and other things, conct cycles throughout cell cycle, exposes active site in CDK, making it more active CDK activating kinase (CAK) - phosphorylates thr160 in CDK, fully activates CDK, happens after cyclin bonding

P53 - tumor suppressor, responsible for regulating cell cycle. Inhiits cell cycle genes. Activates expression of DNA repair genes, apoptosis. Overall funciton is to supress cell cycle progression. Used in G1 (to see if DNA is damaged), G2 (stops cell cycle if DNA is damaged).

With growth factors, mitogens expressed only when mitogens are present, peaks around late G1in restriciton point Cyclin b is used in G2 Cyclin A and E used in G1/S transition if no DNA problems

phosphorylates and inactivate teh cell cycle inhibitor retinoblastoma which is binded to E2F once RB is phosphorylated it no longer binds to E2F which stops acting like inhibitor

longest phase checks if env is good, checks if it got growth factor stim, has 2 checkpoints 1. Restriction point - gateway in late G1 regulates expression of genes needed for cell cycle, looks for tumor supressor (retinoblastoma) and E2F transcription factors once it passes restriction point its commited to S phase 2. G1/S checkpoint looks for DNA damage

G1/S is checpoint in late G1 phase to look for DNA damage Ataxia telangiectasi mutated (ATM) - ser-thr kinaserecognizes double stranded breaks ATR - ser/thr kinase, recognizes damage associiated with DNA SSB and DSB

DSB signals ATM to be phosphoorylated. ATM is kinase. then E2F is phosphorylated, activate apoptosis genes also enhances P53 which increases apoptosis genes P53 increases expression of P21 which is trans factor, inhibits CDK, prevents cell cycle cont Mdm2 is also phos and inactivated. and no longer suppresses p53 If there is SSB then ATR is activated and phosphrylates other kinase, CHK1 This then phos and inhibits CDC 25. This signals to cell to degrade it and suppress cell cycle

Cyclin E/CDK2 and cyclind A/CDK2 increases - more phorphorylation of pRetinoblastoma (further stops it from inhibitind creation of cyclin E/A, CDK1, cdc25), cells got to S phase pRB is phosphorylataed thorugh s g2 and M

is inhibited by RB acts as transcription factor, activates transcription of genes needed for S phase activates Cyclin E, A, Cdk1 and cdc 25

dna replication cyclin A/E and CDK triggers ORCs org of replication complexes start (ORCs) CDK activates MCM2-7 : a helicase- unwinds DNA Dna is replicated high lvls of CDK prevent more replication by binding to ORC

does final check for DNA damage from replication organelles are duplicaed CyclinA/CDK1 initiate spindle pole formation, phos the condensin protien complex - causes chromatin to condense Wee1 - binds to CDK1 and prevents premature mitosis, so cycling can accumulate

intact - CDC25 removes inhibitory phosphate on CDK1 -Wee1 is deactivated -cyclin B - CDK1 drives mitosis Damaged - atm/Atr response - cycling A/CDK1 and Cyclin b/CDK1 stay inactive -Wee1 stays active, inhibits CDC25 which would usually dephos the CDK and activate it - cell repairs or dies

RB stays unphosphorylated (keeps binding to E2f, would usually be phos all the way through cell cycel starting in G1) E2F remains inhibited (phosphorylation of RB activates E2F)

CAK - activates CDKs Wee1 inhibits CDK Cdc 25A - activates S phase CDKs cdc25C - activates mitotic CDKs rb - binds to E2F, prevents transcription of cyclin, cdks and other cell cycle genes p21- binds and inhibits CDKs