2023-10-08 04:00:09
Homologous recombination plays an essential role in genome repair and stability. The main player in this mechanism is the RAD51 protein. Using a mouse model where the homologous recombination activity of RAD51 might be selectively inhibited: the scientists show, in a study published in EMBO Journal, that contrary to what was accepted, the in vivo alteration of the homologous recombination mediated by RAD51, does not promote the development of cancers, but on the contrary prevents it. However, it induces premature aging.
Image d’illustration Pixabay
Genetic instability is a hallmark of both cancer and aging. Homologous recombination is a cellular mechanism that plays an essential role in the repair and maintenance of genome stability. RAD51, which binds to damaged DNA with the help of mediator proteins such as BRCA2, plays a vital role in the central step of homologous recombination. It is in fact RAD51 which searches for sequence homologies with an intact DNA sequence which will be copied, therefore serving as a matrix to repair the damaged DNA.
Due to its importance in maintaining genome stability, homologous recombination is generally considered a mechanism of tumor suppression. Consistent with this theory, many homologous recombination genes (notably BRCA1 and BRCA2) are mutated in tumors, particularly in hereditary breast and ovarian cancers. Surprisingly, despite the central role that RAD51 plays in homologous recombination, its inactivation in tumors is however not observed, which constitutes the “paradox” (A paradox is a proposition which contains or appears to contain a logical contradiction, or a…) RAD51″. One hypothesis is that accessory proteins, such as BRCA1/2, promote the attachment of RAD51 to damaged DNA; Mutations affecting these proteins therefore result in the absence of RAD51 on damaged DNA, which then becomes accessible to other mutagenic repair processes, thereby increasing genetic instability. Therefore, the above-mentioned hypothesis raises the question: does cancer formation result solely from the ablation of homologous recombination, or stimulation (A stimulation is a physical or chemical event that activates Is one or more…) concomitant of mutagenic pathways necessary?
SMRad51, a unique experimental tool
Mouse models are useful tools for studying cancer development as well as aging in vivo. However, RAD51 is an essential gene and its inactivation results in early embryonic lethality. In this work, scientists took advantage of a dominant negative form of RAD51 (SMRad51) that binds DNA with RAD51 and inhibits the activity of homologous recombination of the endogenous RAD51 gene. However, because SMRAD51 attaches to damaged DNA, it still prevents stimulation of alternative mutagenic repair pathways. SMRad51 therefore represents a unique experimental tool allowing the separation of homologous recombination activity from protection once morest mutagenic repair mechanisms. The scientists designed a mouse model with ubiquitous conditional expression (i.e. in all cells of the body) of SMRad51. This gene can only be expressed in this model in the presence of Doxycycline (Dox). This strategy helped overcome the problem of embryonic lethality since homologous recombination can be inactivated following birth by the induction of SMRad51 expression mediated by Dox, added in food.
SMRad51 reveals an effect once morest the development of breast cancer
These mice therefore represent the first specimens to analyze alterations in the functioning of RAD51 in vivo. Suppression of homologous recombination by SMRad51 expression results in replicative stress, systemic inflammation (from the Greek “systema”, “together…). ), depletion of progenitor stem cells, premature aging and reduced lifespan, but, surprisingly, not tumor formation. To better understand the role played by SMRAD51 in cancer in vivo, the mouse model was crossed with the PyMT breast cancer susceptibility model. Expression of SMRad51 decreases both the frequency and size of breast tumors, revealing an effect once morest the development of breast cancer .
Impact of RAD51 in vivo. Wild-type RAD51 protein (top panel) binds damaged DNA, preventing mutagenic repair (SSA and A-EJ), protecting arrested replication forks from degradation, and promoting homologous strand exchange. Strand exchange leads to homologous recombination (HR) and promotes restart of arrested replication forks.
SMRAD51 (lower panel) binds to damaged DNA, preventing mutagenic repair (SSA and A-EJ) and protecting arrested replication forks from degradation. However, SMRAD51 inhibits strand exchange, thereby impairing both HR and restarting arrested replication forks, resulting in replication stress.
Replication stress affects proliferating cells, therefore tumor cells as well as progenitor stem cells, leading to both repression of tumor development and exhaustion of progenitor stem cell pools. Decreased reserves of progenitor stem cells prevent tissue renewal, leading to premature aging. Simultaneous and combined deficiencies of different tissues reduce lifespan. Furthermore, systemic inflammation (which may result from replication stress) can also amplify premature aging and reduced lifespan.
© Bernard Lopez.
The importance of RAD51 in the balance between cancer and aging
Although current dogmas consider deficiency in homologous recombination to be a cause of cancer, this work shows that the specific reduction in homologous recombination mediated by RAD51, without concomitant stimulation of mutagenic alternative repair pathways, primarily leads to aging and not to oncogenesis, and even prevents cancerous development. These data highlight the separation (Generally speaking, the word separation refers to an action consisting of separating something…) and potential competition rather than cooperation between aging and oncogenesis in vivo. This work highlights the importance of RAD51 activity for stem cell homeostasis, prevention of aging and, more generally. , for the balance between cancer and aging.
Reference
In vivo reduction of RAD51-mediated homologous recombination triggers aging but impairs oncogenesis (2023). EMBO Journal.
Gabriel Matos-Rodrigues Vilma Barroca, Ali-Akbar Muhammad, Elodie Dardillac, Awatef Allouch, Stephane Koundrioukoff, Daniel Lewandowski, Emmanuelle Despras, Josée Guirouilh-Barbat, Lucien Frappart, Patricia Kannouche, Pauline Dupaigne, Eric Le Cam, Jean-Luc Perfettini, Paul-Henri Romeo, Michelle Debatisse, Maria Jasin, Gabriel Livera, Emmanuelle Martini, Bernard S. Lopez.
doi.org/10.15252/embj.2022110844
1696758908
#gene #protects #aging #promotes #cancer