The G2 checkpoint serves as a quality control point within a cell’s life cycle, acting before cell division. Located after the cell has duplicated its genetic material in the S phase and just before it enters the M phase (mitosis), this checkpoint ensures all conditions are suitable for the cell to proceed with an accurate and complete division. This regulatory step is fundamental for maintaining the integrity of a cell’s genetic information.
Purpose of the G2 Checkpoint
The primary function of the G2 checkpoint is to verify several conditions necessary for successful cell division. It confirms the full completion of DNA replication, ensuring that every segment of the cell’s genome has been accurately copied exactly once. This prevents the cell from entering mitosis with an incomplete set of genetic instructions, which could lead to an abnormal number of chromosomes in daughter cells, a condition known as aneuploidy.
The checkpoint also scans the newly replicated DNA for any signs of damage or errors. Detecting and addressing such damage before cell division is paramount to preserving genetic stability.
Beyond genetic integrity, the G2 checkpoint also confirms that the cell has accumulated sufficient resources and grown to an adequate size. This ensures the cell possesses the necessary proteins, organelles, and energy reserves to successfully divide into two viable daughter cells. These checks collectively safeguard against the propagation of errors and ensure the health of future generations of cells.
Mechanism of Action
The progression through the G2 checkpoint into mitosis is governed by Maturation-Promoting Factor (MPF). This complex is formed by two key proteins: Cyclin B and Cyclin-dependent kinase 1 (Cdk1). MPF drives the cell into the mitotic phase.
During the G2 phase, Cyclin B levels gradually accumulate, allowing it to bind with Cdk1, forming the inactive pre-MPF complex. This complex is kept inactive by specific inhibitory phosphorylations on Cdk1, primarily at threonine 14 (T14) and tyrosine 15 (Y15) residues, which are added by kinases like Wee1 and Myt1.
When the cell successfully passes all necessary checks, these inhibitory phosphates are removed. Cdc25 phosphatases are responsible for dephosphorylating Cdk1, activating the MPF complex. This activation allows the cell to swiftly transition into mitosis.
Response to Cellular Damage
If the G2 checkpoint identifies problems, such as unreplicated DNA or DNA damage, it triggers a halt in progression. This pause is initiated by specialized sensor proteins, ATM and ATR kinases. ATM primarily detects double-strand breaks in DNA, while ATR responds to a broader spectrum of DNA lesions, including single-stranded DNA regions and stalled replication forks.
Upon activation, these sensor kinases initiate a signaling cascade involving checkpoint kinases Chk1 and Chk2. Chk1 inactivates the Cdc25 phosphatases, preventing them from removing inhibitory phosphates on Cdk1, which ensures MPF remains inactive.
This enforced inactivity of MPF leads to cell cycle arrest, pausing the cell in the G2 phase. This provides the cell with time to activate its DNA repair machinery and fix detected errors before committing to cell division.
Implications for Health and Disease
A properly functioning G2 checkpoint is fundamental for maintaining genomic stability, and its malfunction carries significant consequences for human health. When this checkpoint fails, cells with damaged or incompletely replicated DNA proceed into mitosis. This unchecked progression leads to the accumulation of genetic mutations and chromosomal abnormalities, such as translocations or aneuploidy, a state known as genomic instability.
This genomic instability is a hallmark feature of many cancers, driving the initiation and progression of tumors. Cancer cells frequently harbor defects in various cell cycle checkpoints, but they often become reliant on remaining functional checkpoints, including the G2 checkpoint, to survive. This dependency makes the G2 checkpoint an appealing target for cancer therapies.
Traditional cancer treatments, such as chemotherapy and radiation, induce extensive DNA damage in cancer cells, often overwhelming their repair capabilities and leading to cell death. New therapeutic strategies are emerging that specifically target proteins involved in the G2 checkpoint, such as Chk1 or Wee1 inhibitors. These targeted therapies aim to disable the cancer cells’ remaining checkpoint defenses, sensitizing them to DNA-damaging agents and promoting their destruction.