The dogma
Genetic instability is a characteristic of both cancer cells and ageing. Homologous recombination (HR) is a conserved process that plays a crucial role in maintaining genomic stability, through its function in DNA repair and in the protection and resumption of blocked DNA replication forks. Therefore, HR is generally categorised as a protective mechanism against cancer. Consistent with this classification, causal mutations of cancer have been described in many RH genes, such as BRCA1 and BRCA2, particularly in hereditary breast or ovarian cancer.
However, a study published in the journal Oncogene provides a comprehensive and integrated reassessment of concepts and data on HR actors, not focusing only on HR itself. This new analysis challenges the commonly accepted dogma that HR protects against cancer.
A hypothesis that contradicts the dogma: the role of homologous recombination in responding to replicative stress
Most cancer cells are highly proliferative and must therefore actively replicate their genome; however, the progression of DNA replication forks is constantly hindered by both exogenous factors (UV or ionizing radiations, chemical agents due to pollution, tobacco consumption, chemotherapies ...), or endogenous (conflict with gene transcription, proteins strongly linked to DNA, DNA damage caused by free radicals, regions of the genome that are difficult to replicate...); consequently, cancer cells are subjected to considerable toxic replication stress. That is why the mechanisms enabling cancer cells to cope with deleterious replicative stress should promote tumor progression. Since HR plays a central role in managing replication stress (protection and restart of blocked replication forks), it should promote the survival and proliferation of cancer cells, and consequently tumor progression. In this new analysis, researchers confront the factual data and this provocative point of view with the dogma established for decades.
Homologous recombination and "the RAD51 paradox"
HR is a physiological process that leads to the exchange of DNA segments bearing sequence homologies. The RAD51 recombinase plays the central role in the key step of HR, namely the search for homologous sequences and their exchange (step that gave its name to the mechanism). This role highlights an important concept and subject of this review: 'The RAD51 paradox'. Indeed, HR genes that are mutated in cancer encode HR accessory or mediator proteins. However, despite its central role in HR, the inactivation of RAD51 is not associated with a predisposition to cancer. Conversely, the overexpression of RAD51 is associated with a poor prognosis in different tumour types [1].
The defect of homologous recombination induces mutagenic repair pathways: what is the real cause of carcinogenesis?
The accessory/mediator proteins, whose genes are mutated in cancer, promote RAD51 loading and stabilization of the RAD51 filament, which then leads to HR, but also protects against alternative repair processes that are highly mutator. Inactivation of the mediator/accessory proteins results in the absence of RAD51 on damaged DNA, thus allowing access to these alternative mutator repair pathways, which can preserve some cell viability but generate genetic instability [2–5]. This raises the following question: does a predisposition to cancer result from an inability to carry out HR itself, or from the activation of mutagenic repair processes?
In vivo, specific inactivation of homologous recombination protects against tumor development
Recently, a murine model has made it possible to address this issue. This mouse model expresses a dominant-negative inducible form of RAD51 that specifically inhibits HR without stimulating alternative mutator repair pathways. Remarkably, the decrease in HR in vivo alone induced a pronounced premature aging phenotype, but did not induce tumorigenesis and, on the contrary, counteract [6]. While these data contradict the established dogma, they do support the new hypothesis that RAD51 and HR)facilitate tumor progression in vivo.
In this review, the researchers discuss how the molecular mechanisms of HR can explain this new vision of HR, its consequences, and the 'RAD51 paradox'. Notably, they discuss the non-canonical roles of RAD51. Together, these discussions emphasise the dark side of HR and more specifically RAD51 as a support for tumor development. However, the question of how HR-deficient cancer cells can survive and proliferate remains to be explained. This could lead to the identification of new pharmacological targets for cancer treatment. This reinterpretation of the data could have important implications for the design of anti-cancer strategies. Indeed, this suggests that targeting HR itself could be a promising approach, provided that alternative mutator pathways are not induced. Furthermore, this discussion identifies mutagenic repair pathways, which can compensate for HR defects, as promising targets for new synthetic lethality strategies.
By challenging existing views, this review enables us to redefine and determine the true impact of RAD51 and HR on cancer predisposition and prevention. highlighting the importance of balancing between HR/RAD51 and alternative mutator repair pathways.
The dual roles of HR/RAD51. A. RAD51 plays a central role in HR, repairing damaged DNA and coping with replication stress. These findings support cell viability and proliferation, preventing premature aging. Indeed, the division of progenitor stem cells is required to maintain the stem cell pools, enabling tissue renewal. RAD51 and HR escort the replication of progenitor stem cells, helping maintain stem cell pools. In parallel, RAD51 on damaged DNA protects against mutagenic nonconservative repair processes such as SSA or A-EJ. The absence of RAD51 on damaged DNA impairs HR and concomitantly makes damaged DNA accessible for nonconservative repair. This allows partial rescue of cell viability but induces genetic instability. B. During cancer progression, cells are highly proliferative, thus replicating their genome in the hyperplastic (nontumor) and carcinogenic steps (tumour). Therefore, they are subjected to high replication stress. HR, through its role as a replication fork escort, allows cells to cope with this high replication stress and thus should facilitate cancer progression as soon as the early nontumorigenic step (hyperplasia).
References in the text
- Matos-Rodrigues, G.; Guirouilh-Barbat, J.; Martini, E.; Lopez, B.S. Homologous recombination, cancer and the “RAD51 paradox.” NAR Cancer 2021, 3.
- So, A.; Dardillac, E.; Muhammad, A.; Chailleux, C.; Sesma-Sanz, L.; Ragu, S.; Le Cam, E.; Canitrot, Y.; Masson, J.Y.; Dupaigne, P.; et al. RAD51 protects against nonconservative DNA double-strand break repair through a nonenzymatic function. Nucleic Acids Res. 2022, 50, 2651–2666.
- Stark, J.M.; Hu, P.; Pierce, A.J.; Moynahan, M.E.; Ellis, N.; Jasin, M. ATP hydrolysis by mammalian RAD51 has a key role during homology- directed DNA repair. J Biol Chem 2002, 277, 20185–20194.
- Han, J.; Ruan, C.; Huen, M.S.Y.; Wang, J.; Xie, A.; Fu, C.; Liu, T.; Huang, J. BRCA2 antagonizes classical and alternative nonhomologous end-joining to prevent gross genomic instability. Nat. Commun. 2017, 8, 1470.
- Thomas, M.; Dubacq, C.; Rabut, E.; Lopez, B.S.; Guirouilh-Barbat, J. Noncanonical Roles of RAD51. Cells 2023, 12, 1169.
- Matos‐Rodrigues, G.; Barroca, V.; Muhammad, A.; Dardillac, E.; Allouch, A.; Koundrioukoff, S.; Lewandowski, D.; Despras, E.; Guirouilh‐Barbat, J.; Frappart, L.; et al. In vivo reduction of RAD51 ‐mediated homologous recombination triggers aging but impairs oncogenesis . EMBO J. 2023, 42, 1–21.
Reference
RAD51-mediated homologous recombination is a Pro-tumour driver pathway. Bernard S. Lopez, Oncogene, Online 24 September 2025 - https://doi.org/10.1038/s41388-025-03583-x.
