Evolutionarily Conserved Process of Homologous recombination


Homologous recombination (HR) is an evolutionarily conserved process that plays a pivotal role in the equilibrium between genetic stability and diversity. HR is commonly considered to be error-free, but several studies have shown that HR can be error-prone. Here, we discuss the actual accuracy of HR. First, we present the product of genetic exchanges and the mechanisms of HR during double strand break repair and replication restart. We discuss the intrinsic capacities of HR to generate genome rearrangements by GC or CO, either during DSB repair or replication restart. During this process, abortive HR intermediates generate genetic instability and cell toxicity. In addition to genome rearrangements, HR also primes error-prone DNA synthesis and favours mutagenesis on single stranded DNA, a key DNA intermediate during the HR process. The fact that cells have developed several mechanisms protecting against HR excess emphasize its potential risks. Consistent with this duality, several pro-oncogenic situations have been consistently associated with either decreased or increased HR levels. Nevertheless, this versatility also has advantages that we outline here. We conclude that HR is a double-edged sword, which on one hand controls the equilibrium between genome stability and diversity but, on the other hand, can jeopardize the maintenance of genomic integrity. Therefore, whether non-homologous end joining or HR is the more mutagenic process is a question that should be re-evaluated.

Genomes are routinely challenged with exogenous or endogenous insults of enzymatic, chemical or physical origins. These DNA alterations can generate genetic instability, leading to cell death, senescence, developmental abnormalities and tumour initiation and progression. However, while it is vital to maintain genomic stability, genetic diversity is essential to physiological processes, such as the generation of the immune repertoire or the mixing of parental alleles during meiosis. Additionally, the absence of genetic diversity would constitute an evolutionary dead end. Thus, DNA repair should maintain genomic stability and allow for genetic diversity. Therefore, the accuracy of DNA repair processes is an essential issue.

Homologous recombination (HR) is a process that is conserved in all organisms, playing an essential and pivotal role in genome stability and plasticity. Notably, HR is involved in the reactivation of replication forks that have been blocked and in the repair of DNA double strand breaks (DSBs).

Replication fork progression is routinely challenged by diverse exogenous or endogenous stresses, which ultimately leads to replication fork stalling, collapse or breakage, and triggers the DNA damage response (DDR).

Failures in chromosome replication are thus a primary source of genetic instability. Consistently, in many organisms, including yeast and human cells, both slowing down and blocking fork progression are associated with chromosome breakage and genome rearrangement. Moreover, impediments to fork progression might also challenge the completion of DNA replication, resulting in mitotic defects and multipolar mitotic cells, which then lead to uneven chromosome segregation and thus amplifying the genome instability to the whole genome, including fully replicated regions.

The Products of HR and Models

Consistently with the implication of HR in genome stability maintenance, mutant cells that are defective in HR show elevated mutagenesis and genetic instability. However, in contrast, HR can appear as a mutagenic process per se, in many situations. Such concepts can be understood when considering the products and molecular mechanisms of HR.

The products of HR are gene conversion associated or not with crossing-over. Such products can account for genetic diversity or instability arising through HR.

HR and Replication Forks Reactivation

HR contributes to the robustness of DNA replication by multiple mechanisms and might be viewed as a pathway escorting fork progression. HR can act either at replication forks or at replicated chromatids to ensure the completion of chromosome duplication. First, HR efficiently seals ssDNA gaps that have been left within replicated chromatids after fork passage through DNA lesions. Second, HR is involved in the recovery of arrested replication forks and has the potential to reassemble a functional replisome. While the mechanism of origin-independent loading of a replisome by HR has been extensively characterized in bacteria, its counterpart in eukaryotic cells has only recently begun to emerge.


Regulation of HR should permit the maintenance of genomic stability, allowing genetic diversity but avoiding genetic instability. Depending on the structure of the interacting DNA partners, GC and CO intrinsically possess the capacity to generate genetic variability/instability. In addition to cell cycle regulation, which inhibits HR in the G1 phase and restricts it at the S-G2 phase and the tight cohesion of the sister chromatids that orientates exchange to equal SCE, several additional mechanisms repress HR: mismatch repair, helicases, and p53. Defects in these systems are associated with genome instability and cancer predisposition. The fact that living organisms develop strategies to repress HR underlines the potential dangers of HR excess. Indeed, excess HR does generate mutagenesis and genomic rearrangements. These capacities have been used by cell to generate beneficial genetic diversity, but conversely, many pathological rearrangements are explained by accidental HR.

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