G1/S transition

Stage in cell cycle

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. 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. 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 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.

Another dimer present during mid G1 is composed of retinoblastoma protein (pRB) and transcription factor E2F. When pRb is bound to E2F, E2F is inactive. As cyclin D is synthesized and activates Cdk4/6, the cyclin Cdk targets Rb protein for phosphorylation. Upon phosphorylation, pRb changes conformation so that E2F is released and activated, binding to upstream regions of genes, initiating expression. Specifically, E2F drives the expression of other cyclins, including cyclin E and A, and genes necessary for DNA replication. Cyclin E either phosphorylates more pRb to further activate E2F and promote the expression of more Cyclin E, or it has the ability to increase expression of itself. Cyclin E also interacts with Cdk2 driving the cell cycle to progress from G1 to S phase.

Retinoblastoma (Rb) is a cancer of the eye due to a mutant pRb protein.

Of the four DNA damage checkpoints, two have an additional process for monitoring DNA damage other than activating p53. Before entry into S phase and during S phase, ATM/R also activates Chk1/2 that inhibits Cdc25A, a protein responsible for activating cyclin Cdk dimers. Without cyclin dimer activation, the cell cannot transition through the cycle. These two checkpoints have additional processes for regulation because replicating damaged DNA in S phase can be deleterious to the cell and more importantly, the organism.