The G1/S transition is a stage in the cell cycle at the boundary between the G1 phase, in which the cell grows, and the S phase, during which DNA is replicated. It is governed by cell cycle checkpoints to ensure cell cycle integrity and the subsequent S phase can pause in response to improperly or partially replicated DNA. During this transition the cell makes decisions to become quiescent (enter G0), differentiate, make DNA repairs, or proliferate based on environmental cues and molecular signaling inputs. The G1/S transition occurs late in G1 and the absence or improper application of this highly regulated checkpoint can lead to cellular transformation and disease states such as cancer. During this transition, G1 cyclin D-Cdk4/6 dimer phosphorylates retinoblastoma releasing transcription factor E2F, which then drives the transition from G1 to S phase. The G1/S transition is highly regulated by transcription factor p53 in order to halt the cell cycle when DNA is damaged. It is a "point of no return" beyond which the cell is committed to dividing; in yeast this is called the Start point, and in multicellular eukaryotes it is termed the restriction point (R-Point). If a cell passes through the G1/S transition the cell will continue through the cell cycle regardless of incoming mitogenic factors due to the positive feed-back loop of G1-S transcription. Positive feed-back loops include G1 cyclins and accumulation of E2F in multicellular eukaryotes, and the accumulation of SBF in yeast cells.
Cell cycle overview The cell cycle is a process in which an ordered set of events leads to the growth and division into two daughter cells. The cell cycle is a cycle rather than a linear process because the two daughter cells produced repeat the cycle. This process contains two main phases, interphase, in which the cell grows and synthesizes a copy of its DNA, and the mitotic (M) phase, during which the cell separates its DNA and divides into two new daughter cells. Interphase is further broken down into the G1 (GAP 1) phase, S (Synthesis) phase, G2 (GAP 2) phase and the mitotic (M) phase which in turn is broken down into mitosis and cytokinesis. Following cytokinesis, during G1 phase the cells monitor environment for the potential growth factors, grow larger and once achieve the threshold size (rRNA and overall protein content characteristic for a given cell type) they start progression through S phase. During S phase, the cell also duplicates the centrosome, or microtubule-organizing center, which is critical for DNA separation in the M phase. After complete synthesis of its DNA, the cell enters the G2 phase where it continues to grow in preparation for mitosis. Following interphase, the cell transitions into mitosis, containing four sub stages: prophase, anaphase, metaphase, and telophase. In mitosis, DNA condenses into chromosomes, which are lined up and separated by the mitotic spindle. After duplicate DNA is separated on opposite ends of the cell, the cytoplasm of the cell is split in two during cytokinesis resulting in two daughter cells. The yeast cell cycle goes through similar stages however there is the additional factor of mating to consider. A haploid cell arrests in G1 if it has not passed Start and is exposed to enough mating pheromone, but will progress into S-phase if both of those conditions are not met.
Cell cycle regulation in mammalian cells As with most processes in the body, the cell cycle is highly regulated to prevent the synthesis of mutated cells and uncontrolled cell division that leads to tumor formation. The cell cycle control system is biochemically based so that the proteins of the mitosis promoting factor (MPF) control the transition from one phase to the next based on a series of checkpoints. MPF is a protein dimer made up of cyclin and cyclin-dependent kinase (Cdk), a serine and threonine kinase, which come together at different points in the cycle to control cell progression through the cycle. When cyclin binds to Cdk, Cdk becomes activated and phosphorylates serine and threonine on other proteins causing the activation and degradation of other proteins allowing the cell to transition through the cell cycle.
G1/S transition In mid to late G1 phase, cyclin D bound to Cdk4/6, activates the expression of the S phase cyclin-Cdk components; however, the cell does not want S phase cyclins to become active in G1. Therefore, an inhibitor, protein Slc-1, is present that interacts with the dimer so that the S phase cyclin-Cdk dimer remains inactive until the cell is ready to move into S phase. After the cell has grown and is ready to synthesize DNA, G1 cyclin-Cdks phosphorylate the S phase cyclin inhibitor signaling ubiquitination, resulting in the addition of groups to the inhibitor. Ubiquitination of the inhibitor signals the SCF/proteasome to degrade the inhibitor releasing and allowing the S phase cyclin-Cdk to become activated and the cell moves into S phase. Once in S phase, cyclin-Cdks phosphorylate several factors on the replication complex promoting DNA replication by causing inhibitory proteins to fall off of replication complexes or through activation of components on the replication complex to induce DNA replication initiation.
Retinoblastoma protein (pRB) and the G1/S transition
… excerpt ends here. Continue reading the full article.
