RAD51-mediated homologous recombination is a pro-tumour driver pathway

Abstract

Genetic instability is a hallmark of cancer cells. Homologous recombination (HR) plays a pivotal role in maintaining genome stability through its DNA repair and replication fork escort functions. Therefore, HR is classified as a tumour suppressor pathway. Consistently, many HR genes are mutated in cancer, especially in hereditary breast and ovarian cancer. However, although RAD51 controls the central steps of HR, no RAD51 mutations are associated with cancer predisposition, constituting the “RAD51 paradox”. One of the potential explanations for the “RAD51 paradox” is that mutations affecting mediator/accessory genes (such as BRCA1 or BRCA2) in cancer result in the absence of RAD51 on damaged DNA, leaving access to alternative exclusively mutagenic repair processes, such as single-strand annealing (SSA) or alternative end-joining (A-EJ), which can rescue some cell viability but also increase genetic instability. This raises the question of whether cancer predisposition actually results from HR deficiency itself or from alternative, nonconservative repair pathways. One study assessing this question in a mouse model revealed that decreasing RAD51 HR activity without stimulating SSA or A-EJ in vivo not only does not favour tumorigenesis but rather protects against it. These data suggest that RAD51-controlled HR is not a tumour suppressor but rather favours tumour progression. Cancer cells are highly proliferative, actively replicating their genomes, and are therefore subjected to high replication stress; pathways enabling them to cope with this massive replication stress, such as HR, should help them survive and proliferate, contrary to the belief dogma that HR acts as a tumour suppressor pathway. We propose that HR/RAD51, through its essential role in overcoming replication stress, should facilitate cancer progression as soon as early pretumorigenic hyperplasia states that trigger an active replication program, challenging commonly accepted views.