When it comes to DNA repair, cells have a complex system in place to prioritize which lesions to repair first. This process involves various factors that help the cell determine the level of damage and the importance of repairing specific lesions. Let’s dive into how cells prioritize which DNA lesions to repair first.
DNA Damage Recognition
Cells constantly face DNA damage from various sources such as UV radiation, chemicals, and environmental factors. To prioritize which lesions to repair first, cells rely on a sophisticated system of DNA damage recognition. This involves specialized proteins that scan the DNA for lesions and determine their severity.
- Damage sensing proteins: Proteins like ATM and ATR are responsible for sensing DNA damage and initiating the repair process. These proteins help identify the type and extent of damage, allowing the cell to prioritize repair.
- Checkpoint proteins: Checkpoint proteins like BRCA1 and BRCA2 play a crucial role in assessing the severity of DNA damage and coordinating repair activities. They help determine which lesions require immediate attention.
Severity of the Lesion
Not all DNA lesions are created equal. Some lesions can be more detrimental to the cell’s survival and function than others. Cells prioritize repairing lesions based on their severity and potential impact on cell health.
- Double-strand breaks: Double-strand breaks are considered the most severe type of DNA damage as they can lead to mutations and cell death if left unrepaired. Cells prioritize repairing double-strand breaks to maintain genomic stability.
- Single-strand breaks: Single-strand breaks are also important to repair, as they can cause replication errors and genomic instability. While not as severe as double-strand breaks, cells still prioritize repairing single-strand breaks promptly.
- Base mismatches: Base mismatches are relatively common and can lead to mutations if not repaired. Cells prioritize repairing base mismatches to prevent mutations and maintain DNA integrity.
Cell Cycle Phase
The cell cycle phase also plays a crucial role in determining which DNA lesions to repair first. Cells have specific checkpoints and repair mechanisms activated at different stages of the cell cycle to ensure proper repair and prevent mutations.
- G1 phase: During the G1 phase of the cell cycle, cells assess DNA damage and determine whether it can be repaired or if the cell should enter a state of quiescence or apoptosis. Repair of severe lesions is prioritized during this phase.
- S phase: In the S phase, when DNA replication occurs, cells prioritize repairing lesions that can interfere with replication and lead to mutations. This includes single-strand breaks and base mismatches.
- G2 phase: The G2 phase is another checkpoint where cells assess DNA damage before entering mitosis. Repair of double-strand breaks is prioritized during this phase to maintain genomic stability.
Repair Pathways
Cells have different DNA repair pathways that are specialized for repairing specific types of DNA damage. Based on the type of lesion present, cells activate the appropriate repair pathway to ensure efficient and accurate repair.
- NER (Nucleotide Excision Repair): NER is a pathway used to repair bulky lesions such as UV-induced pyrimidine dimers. Cells prioritize using NER to repair bulky lesions that can distort the DNA helix.
- BER (Base Excision Repair): BER is a pathway used to repair base mismatches and single-strand breaks. Cells prioritize using BER to repair these common types of DNA damage.
- HR (Homologous Recombination): HR is a pathway used to repair double-strand breaks and other complex lesions. Cells prioritize using HR for repairing severe double-strand breaks to ensure genomic stability.
- NHEJ (Non-Homologous End Joining): NHEJ is another pathway for repairing double-strand breaks. While less accurate than HR, cells may prioritize using NHEJ for quick repairs to prevent cell death.
Cellular Stress Response
Cells have evolved to respond to various stressors, including DNA damage, by activating specific signaling pathways that help prioritize repair activities. These stress response mechanisms play a crucial role in determining which DNA lesions to repair first.
- p53 pathway: The p53 pathway is a key player in the cellular stress response to DNA damage. p53 acts as a tumor suppressor and helps prioritize repairing severe lesions by triggering cell cycle arrest or apoptosis if the damage is too extensive.
- ATM/ATR signaling: ATM and ATR kinases are activated in response to DNA damage and help initiate repair pathways. These signaling molecules play a critical role in prioritizing repair activities based on the severity of the lesions.