(from left to right) Dr. Ananya Acharya, Stefan Braunshier and Safa Nasrin, co-authors of the publication.
A collaborative paper published in Science by the team led by Prof. Chaudhuri at the Erasmus MC Cancer Center (Netherlands) and Prof. Cejka at the IRB in Bellinzona, reveals that the anti-recombinase FIGNL1 inhibits DNA repair in BRCA2-deficient cells by removing RAD51 from damaged DNA.
BRCA2 is a protein that plays a crucial role in repairing toxic double-stranded breaks in DNA through a process called homologous recombination (HR). A key step in HR–mediated DNA break repair is the loading of RAD51 onto DNA near the break site. RAD51 then facilitates the identification of a template for DNA repair. The primary function of the BRCA2 tumor suppressor is to promote RAD51 loading onto broken DNA. In people with a BRCA2 mutation, this mechanism doesn’t function properly, resulting in DNA damage and significantly increasing the risk of breast, ovarian, or prostate cancer.
Common chemotherapeutic strategies used to eliminate these tumors include targeting the cell’s residual DNA repair capacity. Often, after several months to years, the tumors stop responding to chemotherapy, a process known as chemoresistance. Research has shown that BRCA2-deficient cancer cells sometimes manage to restore their HR mechanism. This allows them to repair DNA and survive. Until now, it was a mystery how this was possible.
This study, led by Prof. Arnab Ray Chaudhuri and Prof. Petr Cejka, highlights the role of the protein FIGNL1, a known anti-recombinase, in chemoresistance. For cells to remain healthy, the proper amount of RAD51 loading on broken DNA is crucial: without BRCA2, there is too little; without FIGNL1, there is too much, which is similarly deleterious. Interestingly, in the absence of both BRCA2 and FIGNL1, RAD51 loading is restored to almost normal levels. This restoration is mediated by the MMS22L–TONSL complex.
In this article, published in Science, the Chaudhuri group performed all cellular experiments, showing that FIGNL1 loss rescued BRCA2-deficient cells by restoring their DNA repair capacity. The Cejka laboratory (Safa Nasrin, Stefan Braunshier, Dr. Ananya Acharya) conducted complementary in vitro biochemical assays, which uncovered mechanistic insights into the interplay among FIGNL1, BRCA2, and MMS22L–TONSL in maintaining the proper balance of RAD51 loading on broken DNA.
These findings open new avenues for cancer therapy by identifying MMS22L–TONSL as a potential target in BRCA2-mutated, chemoresistant tumor cells.
Article:
FIGNL1 inhibits homologous recombination in BRCA2 deficient cells by dissociating RAD51 filaments
