postreplication repair

Definition

Target type: biologicalprocess

The conversion of DNA-damage induced single-stranded gaps into large molecular weight DNA after replication. Includes pathways that remove replication-blocking lesions in conjunction with DNA replication. [GOC:elh]

Postreplication repair (PRR) is a crucial DNA damage tolerance mechanism that allows cells to bypass lesions that block replication forks. It operates after the initial replication fork stalling, preventing the collapse of the fork and subsequent cell death. PRR primarily involves two distinct pathways: template switching and homologous recombination (HR).

**Template Switching**

Template switching is a relatively simple mechanism that involves the replication fork switching to an undamaged template strand. This process occurs through a series of steps:

1. **Fork Stalling:** When the replicative machinery encounters a DNA lesion, the fork stalls, unable to proceed further.
2. **Fork Regression:** The stalled fork regresses, resulting in a Holliday junction structure. This junction is composed of four DNA strands, with two paired segments from each of the original DNA strands.
3. **Template Switch:** The replication machinery, likely the polymerase, dissociates from the damaged strand and switches to the undamaged template strand. This switch allows the polymerase to continue replicating the DNA using the undamaged strand as a template.
4. **Fork Re-establishment:** The replication fork is re-established, allowing DNA synthesis to continue.

**Homologous Recombination (HR)**

HR is a more complex and error-free pathway that utilizes homologous sequences from sister chromatids to repair DNA damage. HR involves a series of steps:

1. **Double-Strand Break:** A double-strand break (DSB) occurs at the site of the lesion, resulting in a complete separation of the two DNA strands.
2. **Resection:** The 5’ ends of the broken DNA strands are resected by nucleases, creating 3’ single-stranded tails.
3. **Strand Invasion:** The 3’ tail of one strand invades the homologous sister chromatid, forming a displacement loop (D-loop).
4. **DNA Synthesis:** DNA synthesis occurs using the undamaged sister chromatid as a template, extending the invaded strand.
5. **Branch Migration:** The D-loop expands, with the newly synthesized DNA displacing the original strand.
6. **Resolution:** The Holliday junction is resolved, producing two intact DNA molecules.

**Significance of PRR:**

PRR plays a vital role in maintaining genomic stability and protecting cells from the harmful effects of DNA damage. By allowing replication to proceed despite the presence of lesions, PRR prevents replication fork collapse, genomic instability, and ultimately, cell death. PRR pathways are particularly important in cells exposed to DNA damaging agents, such as ultraviolet radiation, ionizing radiation, and chemotherapy drugs.

**Clinical Relevance:**

Defects in PRR pathways can contribute to various diseases, including cancer. Mutations in genes involved in PRR, such as BRCA1 and BRCA2, are frequently found in breast and ovarian cancers. These mutations increase the risk of developing cancer by impairing the ability of cells to repair DNA damage, leading to genomic instability and uncontrolled cell growth.

**Conclusion:**

Postreplication repair is an essential mechanism for maintaining genome integrity and ensuring the proper transmission of genetic information. The two main PRR pathways, template switching and HR, provide distinct strategies for bypassing DNA lesions during replication. Understanding the intricacies of PRR is crucial for comprehending the mechanisms of DNA damage tolerance and the development of targeted therapies for cancer and other diseases associated with DNA repair defects.'
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