Cell Cycle Control & DNA Damage Response PDF

Slide 3: The G1/S transition is a critical point of control for the cell cycle – this is the decision of whether the cell initiates DNA synthesis. Know the importance of the G1/S point. You should know that mitogenic growth signaling modulates the entry into the S phase and that various factors, suc...

Slide 3: The G1/S transition is a critical point of control for the cell cycle – this is the decision of whether the cell initiates DNA synthesis. Know the importance of the G1/S point. You should know that mitogenic growth signaling modulates the entry into the S phase and that various factors, such as the retinoblastoma protein (RB) and its phosphorylation state assist the control of the G1/S transition. Slide 4: What you need to know is that many signaling pathways converge on cyclin-dependent kinases, to activate or inhibit these kinases and control the cell cycle progression. Slide 5: Cell cycle arrest in interphase is an important quality control checkpoint in the cell cycle. If a cell has DNA damage, this cell should not continue to progress through the cell cycle and pass that damaged DNA to the daughter cells. This may lead to cancer. There are mechanisms that respond to DNA damage by stopping the cell cycle in interphase. This gives the cell time to either repair the damage or to undergo apoptosis (programmed cell death). Double- strand DNA breaks activate the ATM pathway, and if the DNA is not repaired, the cell undergoes G1 arrest and/or apoptosis. Single-strand DNA damage activates the ATR pathway, and if the DNA is not repaired, the cell has an S-phase or G2-phase arrest. Slide 6: Single-strand DNA damage, for example, from UV radiation resulting in cross-links, can activate the ATR pathway, which leads to phosphorylation of the checkpoint 1 (Chk1) factor. This in turn can phosphorylate cdc25, making it bind to 14-3-3 and be exported from the nucleus. Once outside the nucleus, cdc25 cannot counteract the inhibitory phosphorylation from cdks. This leads to G2-phase arrest. Degradation of the phosphorylated cdc25 also leads to S-phase and G2- phase arrest. Slide 7: Double-strand DNA damage, for example, from ionizing radiation (cosmic rays, gamma rays, neutrons, etc.), can activate the ATM pathway, which leads to phosphorylation of the checkpoint 2 (Chk2) factor. This in turn phosphorylates and stabilizes p53 (a transcription factor often mutated in cancer) that promotes expression of p21. p21 causes G1-phase arrest. Degradation of cdc25 can also occur. Some mutations of p53 allow cells to divide even with DNA damage, which is why this type of mutations is associated with cancer. Slide 8: Fundamental points. The cell cycle, particularly the G1 to S transition is tightly controlled by a variety of signals. Interphase cell cycle arrest is a response to DNA damage, stops cell division so that cells can either repair damage or undergo programmed cell death (apoptosis). Interphase cell cycle arrest is through the ATR and ATM pathways. ATR is activated by single- strand DNA defects; ATM is activated by double-strand DNA breaks.