negative regulation of mitotic cell cycle DNA replication

Definition

Target type: biologicalprocess

Any process that stops, prevents or reduces the frequency, rate or extent of mitotic cell cycle DNA replication. [GO_REF:0000058, GOC:mtg_cell_cycle, GOC:TermGenie, PMID:1234]

Negative regulation of mitotic cell cycle DNA replication is a crucial process that ensures the proper timing and fidelity of DNA duplication during cell division. This intricate regulatory mechanism involves a complex interplay of proteins and signaling pathways that control the initiation and progression of DNA replication. Key aspects of this process include:

- **Licensing of origins of replication:** During G1 phase, origins of replication are "licensed" to initiate DNA replication by the assembly of the pre-replication complex (pre-RC). This complex includes origin recognition complex (ORC), Cdc6, Cdt1, and MCM proteins.
- **Activation of origins:** In S phase, the pre-RC is activated, leading to the recruitment of additional factors and the unwinding of DNA at the origin. This step involves phosphorylation of Cdc6 and Cdt1, which promote their release from the origin.
- **Initiation of DNA replication:** Once DNA is unwound, DNA polymerase and other replication machinery assemble at the origin to initiate DNA synthesis.
- **Checkpoint control:** Several checkpoints ensure that DNA replication occurs accurately and efficiently. These checkpoints monitor DNA integrity and prevent the initiation of replication until any damage is repaired.
- **Termination of replication:** After DNA replication is completed, mechanisms are in place to prevent re-replication of the same DNA segment. This involves inactivation of licensing factors and the degradation of key replication proteins.

Negative regulation of this process is essential to prevent premature or uncontrolled DNA replication, which can lead to genomic instability and cell death. Mechanisms involved in negative regulation include:

- **Inhibition of licensing factors:** The activity of licensing factors, such as Cdc6 and Cdt1, is tightly controlled. Phosphorylation and degradation of these factors can inhibit their ability to bind to origins and promote pre-RC assembly.
- **Regulation of cyclin-dependent kinases (CDKs):** CDKs play a critical role in regulating the cell cycle. Their activity is tightly controlled by cyclins and other regulatory proteins. CDKs can phosphorylate licensing factors and other proteins involved in DNA replication, promoting or inhibiting their activity.
- **Checkpoint activation:** When DNA damage is detected, checkpoints are activated to halt DNA replication. This allows time for repair before proceeding with the cell cycle.
- **Degradation of key replication proteins:** After DNA replication is complete, some proteins involved in replication are targeted for degradation, ensuring that replication does not occur again.

By precisely regulating these steps, cells ensure the accurate duplication of their genetic material, which is essential for maintaining genomic integrity and for normal cell growth and development.'
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Proteins (1)

Compounds (3)