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MolBio (Fach) / Lecture 8 (Lektion)
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- Def. Cell cycle life cycle of a cell, period between successive divison of a cell [successive = aufeinanderfolgend]
- Cell cycle in prokaryotes Binary fission = normal life cycle of a prokaryote, which involves: -Replication phase (R-phase = C-period) -Division phase (D-phase = D-period) -Interval phase (I-Phase = B-Period)
- R-Phase / C-Period duration to replicate the bacterial genome [~40 min for E.Coli]
- D-Phase / D-Period segregation of daughter chromosome + cell components into daughter cells initiated by FtsZ-Proteins -form the Z-Ring, which forms the septum
- I-Phase / B-Period Period between division & chromosome replication
- Cell cycle for a typical human cell (~24h total cell cycle Duration) G1 = 11h S = 8h G2 = 4h M = 1h
- G1-Phase after cell division first phase in Interphase growth and biosynthesis acivity phase duration highly variable series of checks before entering S-phase
- S-Phase replication of DNA
- G2-Phase series of checks before entering the M-Phase
- M-Phase cell division -Karyokinesis (Mitosis) -Cytokinesis
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- G0-Phase "resting phase" -> exit the cell cycle, survive longer quiescent ("sleeping") cells may re-enter the cell cycle senescent ("ageing") don´t re-enter the cell cycle most somatic cells stay in G0-Phase (quiescent)
- CDK Cyclin-dependent-kinases no activity until associated with a cyclin cyclin concentration fluctuates, CDK concentration is stable different CDK => different cyclin necessary => different protein gets phosphorylated
- Main CDK-Complexes G1 cyclin-CDK S-Phase cyclin-CDK mitotic cyclin-CDK
- Cell Cycle Chekpoints (def.) Cascade of signalling events Surveillance mechanisms which monitor major events: -growth (cell size) -replication -integrity of chromosomes (-Vollständigkeit) -accurate segregation
- G1/restriction checkpoint Checks: cell size, nutrients, growth factors, DNA damage If Damage is found: G1 arrest or G0 Phase After the restriction checkpoint the cell cycle is no longer depending on growth factors
- S-Phase checkpoint Checks: DNA damage (spontaneous mutations), stabilization of replication forks If damage is found: replication is stoped until the problem is solved
- G2-Phase checkpoint checks: DNA damage (prevents cell from entering M-Phase with DNA damage) [highly conserved proteins] If damage is found: p53 activates gene expression to induce apoptosis
- M-Phase checkpoint checks: mitotic spindle assembly If damage is found: arrest in anaphase
- P53 nuclear, DNA-binding phosphoprotein, transcription factor can be activated by: -increasing proteins half-life -increasing rate of translational initiation -posttranslational modifications -alternative splicing can induce cell cylce stops and apoptosis tumor suppressor
- DNA-Reparation (in General) exists in pro- and eukaryotes DNA repair <> cell cycle (closely tied) checkpoint mechanisms
- DNA Damage response DNA damage can result in 4 different ways: 1)repair 2)tolearance 3)Apoptosis 4)Checkpoint activation -> cell cycle arrest
- Mismatch repair (MMR) Repair of DNA replication errors -removes base mismatches and small insertion/deletion loops MMR is strand specific
- Human pathology (MMR) Germ line allelic variants in MMR genes -MLH1,MSH2,MSH6 or PMS2 predispose to hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome
- Nucleotide excision repair (NER) repairs damage by enviromental factors (e.g. UV-light inducted DNA damage) two repair pathways: -for transcriptional active DNA (TC-NER) -for global genomic (GG-NER)
- Human pathology: NER: Xeroderma pigmentosum Name: Xeroderma pigmentosum Symptoms: -Skin photosensitivity, elevated cancer risks, mental retardation Mechanism: -XP-proteins have functions in NER --allelic variants leads to this
- Human pathology: NER: Cockayne Syndrome (CS) Name: cockayne syndrome Symptoms: -mental and developmental retardation -photosensitivity -permature agein and progressive neurodegeneration Mechanism: -defective XP and CS proteins leads to defects in NER + BER (mitochondrial base excision repair)
- Base excision repair (BER) removes damaged bases initiated by DNA glycosylase two pathways: short (removes one base lesions), long (removes 2-10 base lesions) can repair: -oxidized bases -alkylated bases -deaminated bases -inappropriately incorporated uracil -single strand DNA breaks
- Homologous recombination repair (HR) can repair DSB uses homologous DNA template -therefore highly accurate HR more active in S & G2 Phase
- Non-homologous end joining (NHEJ) can repair DSB rejoins broken ends -mostly loss of some nucleotides NHEJ more active in G1 - Phase
- Human pathology (HR + NHEJ): Ataxia telangiectasia Name: Ataxia telangiectasia Symptoms: -telangiectasia in the eye (Small dilated blood vessels) -cerebellar degeneration -immunodeficiency Mechanism: -Allelic variants in ATM-gene (ATM protein is important for repair of DSB, cell-cycle regulation and Apoptosis)
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- Cell aging (def) irreversible arrest of cell proliferation considered irreversible
- Apoptosis programmed cell death Leads to -fragmentation of DNA -shrinkage of the cytoplasm -membrane changes -without damage to neighboring cells Intrinsic pathway: -done by proteases caspases (produced by inactive procaspases, activated by cleavage) -protease cascade is irreversible Extrinsic pathway: -activation from outside
- After the cell death pathway is activated cell shrinks cytoskeleton collapses nuclear envelope disassembles nuclear DNA breaks into fragments cell surface is altered -> Phagocytosis