What is Difference Between Nonhomologous End Joining and Homologous Direct Repeat

The key difference between nonhomologous end joining and homologous direct repeat is that nonhomologous end joining is a pathway that repairs double-strand breaks in DNA that does not require a homologous template to guide repair, while homologous direct repeat is a pathway that repairs double-strand breaks in DNA that requires a homologous template to guide repair.

DNA repair is a process where a cell identifies and corrects damages to the DNA molecules. Generally, normal metabolic activities and environmental factors such as radiation can cause DNA damage. These factors can result in tens of thousands of individual molecular lesions per cell per day. DNA double-strand breaks repair pathways are DNA repair pathways in biological cells. There are two DNA double-strand breaks repair pathways as nonhomologous end joining and homologous direct repeat.

CONTENTS

1. Overview and Key Difference
2. What is Nonhomologous End Joining  
3. What is Homologous Direct Repeat
4. Similarities – Nonhomologous End Joining and Homologous Direct Repeat
5. Nonhomologous End Joining vs Homologous Direct Repeat in Tabular Form
6. Summary – Nonhomologous End Joining vs Homologous Direct Repeat

What is Nonhomologous End Joining?

Nonhomologous end joining (NHEJ) is a pathway that repairs double-strand breaks in DNA and does not require a homologous template to guide repair. This pathway was found by Moore and Haber in 1966. This pathway is typically guided by short homologous DNA sequences (microhomologies) that are often present in single-stranded overhangs on the ends of double-strand breaks. When the overhangs are compatible, the NHEJ pathway repairs the double strands break accurately. However, when the overhangs are not perfectly compatible, it leads to imprecise repair that will cause loss of nucleotides. The inappropriate NHEJ pathway can lead to translocations, telomere fusions, and hallmarks of tumor cells.

NHEJ pathway has three main steps: end binding & tethering, end processing, and ligation. In mammals, proteins called Mre11-Rad50-Nbs1 (MRN), DNA- PKcs, Ku (Ku70 & 80) are involved in end bridging. The end processing step involves the removal of mismatched or damaged nucleotides and the resynthesis of DNA by DNA polymerases (gap-filling). Removal of mismatched or damaged nucleotides is carried out by nucleases such as Artemis. The X family DNA polymerases Pol  λ  and μ in mammals carry out the gap filling. End processing is not necessary if the ends are already compatible and have 3’hydorxyl or 5’phosphate termini. Furthermore, the final ligation step is performed by ligation complex IV that consists of DNA ligase IV and its cofactor XRCC4.

What is Homologous Direct Repeat?

Homologous direct repeat (HDR) is a pathway that repairs double-strand breaks in DNA with the use of a homologous template to guide repair. The most common way of homologous direct repeat is through homologous recombination. HDR mechanism is only possible when there is a homologous piece of DNA in the nucleus, mostly in the G2 and S phase of the cell cycle.  The biological pathway of HDR starts with phosphorylation of histone protein called H2AX in the area where DNA double-strand break occurs. This attracts other proteins to the damaged location. Then MRN complex binds to damaged ends and prevents chromosomal breaks. MRN complex also keeps broken ends together. Later, DNA ends are processed in such a way that unnecessary residuals of chemical groups are removed, and single-strand overhangs are formed.

Every piece of single-stranded DNA is covered by the protein called RPA, and its function is to keep single-stranded DNA pieces stable. After this, Rad51 replaces the RPA protein. Moreover, when working together with BRCA2, Rad51 couples a complementary DNA piece that invades the broken DNA strand to form a template for DNA polymerase. The DNA polymerase is held onto DNA by another protein known as PCNA. Ultimately, the polymerase synthesizes the missing part of the broken strand. Furthermore, when the broken strand is resynthesized, both strands need to uncouple again. Models for numerous ways of uncoupling are suggested. After strands are separated, the process is completed.

What are the Similarities Between Nonhomologous End Joining and Homologous Direct Repeat?

• Nonhomologous end joining and homologous direct repeat are two DNA double-strand breaks repair pathways.
• MRN complex is involved in both pathways.
• Nucleases are involved in both pathways.
• DNA polymerases are involved in both pathways.
• These mechanisms can be found in both prokaryotes as well as eukaryotes.
• They are both crucial mechanisms for cell survival.

What is the Difference Between Nonhomologous End Joining and Homologous Direct Repeat?

Nonhomologous end joining is a pathway that repairs double-strand breaks in DNA that does not require a homologous template to guide repair, while homologous direct repeat is a pathway that repairs double-strand breaks in DNA using a homologous template. Thus, this is the key difference between nonhomologous end joining and homologous direct repeat. Furthermore, homologous recombination is not involved in nonhomologous end joining, while homologous recombination is involved in homologous direct repeat.

The below infographic presents the differences between nonhomologous end joining and homologous direct repeat in tabular form for side by side comparison.

Summary – Nonhomologous End Joining vs Homologous Direct Repeat

DNA repair can be done by different mechanisms such as direct reversal, single strand damage repair, double-strand breaks repair, and translesion synthesis. Nonhomologous end joining and homologous direct repeats are two DNA double-strand breaks repair pathways. Nonhomologous end joining does not require a homologous template to guide the DNA repair pathway. Homologous direct repeat is a pathway that requires a homologous template to guide DNA repair. So, this is the key difference between nonhomologous end joining and homologous direct repeat.

Reference:

1. “Non-Homologous End Joining.” An Overview | ScienceDirect Topics.
2. “Homology Directed Repair.” An Overview | ScienceDirect Topics.

Image Courtesy:

1. “Non homologous end joining and microhomology mediated end joining” By Cynth3004 at English Wikipedia (CC BY-SA 3.0) via Commons Wikimedia
2. “Double-strand break repair models that act via homologous recombination” By Camille Gelot, Indiana Magdalou, and Bernard S. Lopez – https://doi.org/10.3390/genes6020267 (CC BY 4.0) via Commons Wikimedia