Homology directed repair (Homologous recombination)

Homology directed repair (HDR) is a mechanism in cells to repair double-strand DNA lesions.

Homologous recombination is a type of genetic recombination in which genetic information is exchanged between two similar or identical molecules of double-stranded or single-stranded nucleic acids.

It is usually DNA as in cellular organisms but may be also RNA in viruses.

The most common form of HDR is homologous recombination. 

Homologous recombination refers to the process through which genetic information is exchanged between two similar or identical DNA molecules, such as during meiosis to generate genetic diversity.

In homologous recombination, the intact sister chromatid is used as a template to re-synthesize the DNA sequence and repair areas that are broken.

Homologous recombination is important to the integrity of the genome.

With homologous recombination deficiency (HRD) , mutations in BRCA1, or BRCA2, make their cells unable to repair, double-stranded DNA brakes, become unstable genomically and lead to cellular death.

Homologous recombination is widely used by cells to accurately repair harmful DNA breaks that occur on both strands of DNA, known as double-strand breaks (DSB), in a process called homologous recombinational repair (HRR).

Homologous recombination also produces new combinations of DNA sequences during meiosis, the process by which eukaryotes make gamete cells, like sperm and egg cells.

The HDR mechanism can only be utilized  by cells when there is a homologous piece of DNA present in the nucleus.

Homologous recombination factors are involved in the repair of DNA double strand breaks and repair of DNA interstrand crosslinks, and the recovery of stalled and broken replication forks.

HR is one of the two major pathways for the repair of double strand brakes induced by both endogenous and exogenous sources.

These new combinations of DNA represent genetic variation in offspring, which in turn enables populations to adapt during the course of evolution.

Homologous recombination is also used in horizontal gene transfer to exchange genetic material between different strains and species of bacteria and viruses. 

Once the homologous region is found, the two DNA molecules are joined by strand exchange – the broken end of one DNA molecule invades the homologous region of the other DNA molecule, and base pairing occurs: Adenine pairs with Thymine; Guanine pairs with Cytosine.

Enzymes then cleave the new double-helical structures created by strand exchange, releasing the recombined DNA molecules.

The result of homologous recombination is the reciprocal exchange of genetic material between two DNA molecules. 

Homologous recombination is essential for a number of critical biological functions such as chromosome segregation and repair of damaged DNA.

After a double-strand break occurs, sections of DNA around the 5′ ends of the break are cut away in a process called resection. 

Subsequently an overhanging 3′ end of the broken DNA molecule then invades a similar or identical DNA molecule that is not broken. 

After strand invasion, a sequence of events may follow either of two main pathways: the double-strand break repair pathway or the synthesis-dependent strand annealing pathway. 

Homologous recombination that occurs during DNA repair tends to result in non-crossover products, restoring the damaged DNA molecule as it existed before the double-strand break.

Homologous recombination repairs double-strand breaks in DNA caused by ionizing radiation or DNA-damaging chemicals.

Double-strand breaks can cause large-scale rearrangement of chromosomes in somatic cells, which can in turn lead to cancer.

In addition to repairing DNA, homologous recombination also helps produce genetic diversity when cells divide in meiosis to become specialized gamete cells—sperm or egg cells.

It facilitates chromosomal crossover, in which regions of similar but not identical DNA are exchanged between homologous chromosomes, which can give offspring an evolutionary advantage.

Chromosomal crossover often begins when a protein called Spo11 makes a targeted double-strand break in DNA.

These double-strand break sites are non-randomly located on the chromosomes; usually in intergenic promoter regions and preferentially in GC-rich domains.

These double-strand break sites often occur at recombination hotspots, in regions on chromosomes that are about 1,000–2,000 base pairs in length and have high rates of recombination. 

The absence of a recombination hotspot between two genes on the same chromosome often means that those genes will be inherited by future generations in equal proportion: This linkage between the two genes is greater than would be expected from genes that independently assort during meiosis.

Homologous recombination repair attempts occur in DNA before the cell enters meiosis during the S and G2 phases of the cell cycle.

Double-strand breaks can be repaired through homologous recombination, polymerase theta-mediated end joining (TMEJ) or through non-homologous end joining (NHEJ).

Homologous recombination repairs DNA before the cell enters meiosis (M phase). 

It occurs during and shortly after DNA replication, in the S and G2 phases of the cell cycle, when sister chromatids are more easily available.

RNA recombination appears to be a major driving force in determining (1) genetic variability within a CoV species, (2) the capability of a CoV species to jump from one host to another, and (3), the emergence of novel CoVs.

Recombination in RNA viruses appears to be an adaptation for coping with genome damage.

Without proper homologous recombination, chromosomes often incorrectly align for the first phase of cell division in meiosis, causing chromosomes to fail to properly segregate in a process called nondisjunction. 

Nondisjunction can cause sperm and ova to have too few or too many chromosomes. 

Down’s syndrome, which is caused by an extra copy of chromosome 21, is one of many abnormalities that result from such a failure of homologous recombination in meiosis:nondisjunction.

Deficiencies in homologous recombination have been strongly linked to cancer formation: each of the cancer-related diseases Bloom syndrome, Werner syndrome and Rothmund–Thomson syndrome are caused by malfunctioning copies of RecQ helicase genes involved in the regulation of homologous recombination.

Decreased rates of homologous recombination cause inefficient DNA repair, and can also lead to cancer: BRCA1 and BRCA2, two similar tumor suppressor genes whose malfunctioning has been linked with considerably increased risk for breast and ovarian cancer. 

Cells missing BRCA1 and BRCA2 have a decreased rate of homologous recombination and increased sensitivity to ionizing radiation, suggesting that decreased homologous recombination leads to increased susceptibility to cancer.

The only known function of BRCA2 is to help initiate homologous recombination.

Tumors with a homologous recombination deficiency are described as homologous recombination-positive.

The ability of organisms to perform homologous recombination is universally conserved across all domains of life.

Homologous recombination proficient (HRP) cancer cells are able to repair the DNA damage, which is caused by chemotherapy

Cancer cells with BRCA mutations have deficiencies in homologous recombination, and drugs to exploit those deficiencies have been developed and used successfully.

Olaparib, a PARP1 inhibitor, shrunk or stopped the growth of tumors from breast, ovarian and prostate cancers caused by mutations in the BRCA1 or BRCA2 genes, which are necessary for HR. 

In the absence of BRCA1 or BRCA2 other types of DNA repair mechanisms must compensate for the deficiency of HR, such as base-excision repair (BER) for stalled replication forks or non-homologous end joining (NHEJ) for double strand breaks.

Horizontal gene transfer is the primary mechanism for the spread of antibiotic resistance in bacteria.

Homologous recombination is a process by which DNA strands are exchanged and joined between two similar chromosomes or sister chromatids. 

It involves the exchange of genetic material between two DNA molecules with similar or identical sequences.

The process of homologous recombination occurs in several steps:

First, the DNA molecule undergoing recombination undergoes a double-stranded break, which is initiated by endonucleases. 

The break creates two ends that are at risk of degradation, but protection proteins stabilize them and prevent this degradation.

Subsequently, the end of one DNA molecule searches for and finds a homologous region on the other DNA molecule. 

This homology search is facilitated by proteins known as RecA or RAD51 proteins. 

These proteins bind to the first DNA molecule and search the second molecule for a sequence that is identical or near-identical to the broken end.

It is a high-fidelity, template dependent repair process during the S and G2 phases of the cell cycle, when a donor DNA molecule with extensive sequence homologous to the broken DNA is available as a template for repair.

This occurs mostly in G2 and S phase of the cell cycle. 


HDR suppresses the formation of cancer. 


It maintains genomic stability by repairing broken DNA strands.


Every piece of single stranded DNA is covered by the Replication Protein A.


Replication Protein A keep the single stranded DNA pieces stable until the complementary piece is resynthesized by a polymerase. 


The polymerase synthesizes the missing part of the broken strand. 


HDR and other mechanisms repair double strand breaks. 

Germline mutations in genes encoding homologous recombination proteins, are associated with cancer predisposition, developmental disorders, and premature aging.
Specifically, the germline pathogenic variants in ATM, BRCA1 , BRCA2, and PALB2, are known to cause a predisposition to breast, ovarian, prostate, pancreas and gastric cancer (in the presence of H.pylori).

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