RAD51

AMSTERDAM, July 24, 2023 /PRNewswire/ -- LUMICKS, a cutting-edge life science tools company and the leading supplier of dynamic single-molecule and cell avidity analysis instruments, today announced the publication of ground-breaking cancer research in Nature. The research, enabled by LUMICKS' C-Trap® dynamic single-molecule analysis technology, reveals new crucial insights into DNA repair mechanisms associated with cancer. Individuals with mutations in DNA repair genes such as BRCA2 and RAD51 paralogs, have an increased risk of developing breast, ovarian and prostate cancers, the most prevalent forms of cancers in adults. Breast cancer alone caused 685,000 deaths in 2020 and accounted for 12.5% of all cancer diagnoses. While its link to cancer has been widely demonstrated, the mechanism of action of key DNA repair proteins such as the RAD51 paralogs, remained a mystery until no­w. Uncovering the mechanism of action of these key proteins is critical to expedite the development of new cancer-fighting strategies that can improve clinical outcome for patients. This research, published in Nature on June, 21st 2023 and titled "Structure and mechanism of action of the RAD51BCD-XRCC2 tumor suppressor complex" was led by renowned cancer researchers Stephen West and Simon Boulton, from the Francis Crick Institute, London, UK. The study provided novel insights into the role of RAD51BCD-XRCC2 complex (BCDX2) in DNA repair and cancer avoidance. The findings shed new light into how BCDX2 promotes DNA repair by orchestrating the dynamic assembly of RAD51 filaments, a crucial step for maintaining genome stability. LUMICKS C-Trap® played a pivotal role in this study, allowing researchers to directly observe in real-time the dynamic behavior of the BCDX2 complex and its relationship to RAD51, elucidating the link between the structure of the complex to its role and mechanism for the first time. This study also demonstrated the power of complimenting Google DeepMind AlphaFold2 and Cryo-EM structural methods with Dynamic Single-Molecule analysis to reveal crucial insights into the mechanism of action of complex biological systems. This new understanding of the BCDX2 complex's role could significantly enhance treatment strategies for cancer patients. These findings suggest that PARP inhibitors, a class of drugs used in cancer treatment, may also be effective against cancers associated with BCDX2 complex mutations. Furthermore, screening for variants in the BCDX2 complex could provide invaluable insights for families with a history of cancer. By identifying these genetic variants, their future risk profile could be better assesses and potentially more personalized prevention and treatment strategies could be developed. "We are honored that LUMICKS' C-Trap technology is employed in the fight against cancer and enabled this research in Nature," said Andrea Candelli, PhD, Chief Scientific Officer at LUMICKS. "The unique ability of the C-Trap to visualize, in real-time the dynamics of complex biological systems such as the DNA repair mechanism, will open up new strategies for cancer intervention and therapies." Luke Greenhough, PhD, co-first author and postdoctoral researcher at the Francis Crick Institute, is quoted as saying: "For the first time, we've been able to show the direct links between structure, function and why mutations in any of the components of BCDX2 leads to cancer. We now understand its crucial role in DNA repair, which explains why mutations can lead to cancer." About LUMICKS LUMICKS is a leading life science tools company that develops novel equipment for Dynamic Single-Molecule and Cell Avidity analysis, two rapidly emerging areas in biology research and immuno-oncology. LUMICKS' tools allow researchers to build the crucial and yet unfinished bridge between structure and function at both a molecular and a cellular level. This is achieved by applying and measuring forces around biological interactions, enabling the detailed real-time analysis of underlying biological mechanisms. The LUMICKS' C-Trap® instrument use optical tweezers, combined with fluorescence microscopy. The C-Trap enable researchers to manipulate, visualize and thus unravel complex biological processes in real-time. Visit to find out more about LUMICKS and the different solutions they provide. SOURCE Lumicks

Researchers have outlined the structure and function of a protein complex which is required to repair damaged DNA and protect against cancer. In a new paper published today in Nature, researchers at the Francis Crick Institute have outlined the structure and function of a protein complex which is required to repair damaged DNA and protect against cancer. Every time a cell replicates, mistakes can happen in the form of mutations, but specialised proteins exist to repair the damaged DNA. People with mutations in a DNA repair protein called BRCA2 are predisposed to breast, ovarian and prostate cancers, which often develop at a young age. In the clinic, these cancers are treated with a drug that inhibits PARP, another protein needed for DNA repair. Recent work shows that defects in several other proteins can cause inheritable breast and ovarian cancers or Fanconi anaemia, a blood disorder that can lead to different cancers, including leukaemia. The researchers used cryo-electron microscopy to reveal the atomic structure of four of these proteins, which come together to form a complex called BCDX2. This allowed them to map mutations associated with cancer on the 3D structure, revealing the important regions of the complex, and why certain mutations prevent DNA repair, leading to an instability in a person's genes and cancer. In addition, the researchers discovered BCDX2's role in the cell, finding that it acts as a 'molecular chaperone' -- it helps target another protein called RAD51, causing it to recognise and assemble at regions where DNA repair needs to take place. Together, BRCA2, BCDX2 and RAD51 are the main players in the process that repairs damaged DNA -- called 'homologous recombination'. The research shows that BCDX2 is just as important for repairing DNA as BRCA2, suggesting mutations should also be routinely screened for. Luke Greenhough, co-first author and postdoctoral research assistant at the Crick, said: "For the first time, we've been able to show the direct links between structure, function and why mutations in any of the components of BCDX2 leads to cancer. We now understand its crucial role in DNA repair, which explains why mutations can lead to cancer." Eric Liang, co-first author and postdoctoral fellow at the Crick, said: "Just five years ago we wouldn't have been able to do this -- the rapid advance of technology has made this research possible. DeepMind's AlphaFold2 (a computer programme which can predict a protein's 3D structure), cryo-EM and high-resolution imaging techniques allowed us to gather the full picture of structure and function for this key protein complex. It was a very collaborative project, spanning multiple labs and technical teams across the Crick." The research today could help inform the best line of treatment for people living with cancer. Steve West, group leader of the DNA Recombination and Repair Laboratory at the Crick, said: "BRCA2 is well characterised and known to increase the risk of cancer, especially breast and ovarian cancers. It's mutated in 15-20% of inheritable cancer cases so is regularly screened for. "Our research has shown that BCDX2 is also crucial for DNA repair and acts in the same pathway as BRCA2. For people with cancers caused by defects in BCDX2, PARP inhibitors are also likely to be effective. Our findings suggest that people with a family history of these cancers should be screened for mutations in the proteins making up BCDX2 to get a full picture of their risk." The researchers are now hoping to shed light on another protein complex, CX3, which is also involved in cancer. Putting all these insights together will allow a better understanding of genes which put people at a greater risk of cancer and help with targeted treatment.

Nitpicker/Shutterstock Bristol Myers Squibb entered two separate research collaboration and licensing deals, one with San Francisco-based SyntheX and the second with London’s Autolus Therapeutics. This first partnership will leverage SyntheX’s ToRNeDO platform for protein degradation. The platform discovers molecular glue-based protein degraders using pre-specified E3 ligases and neosubstrates. Molecular glue degraders are compounds that organize interactions between a target protein and an E3 ubiquitin ligase, which causes the degradation of the target protein. Ubiquitin attaches to obsolete proteins, signaling to cells that it’s time for them to be disposed of by breaking them down into their component molecules. BMS is paying upfront cash and an investment in the company. SyntheX is eligible for up to $550 million in performance-based milestones. It is also eligible for royalties based on worldwide net sales of any subsequent commercial products. Maria Soloveychik, Ph.D., SyntheX’s co-founder and CEO said the company looks forward to combining its ToRNeDO platform with BMS's clinical development expertise as "we work to discover and deliver the next-generation of TPD therapies for patients in need.” The company’s pipeline focuses on oncology and includes STX100 targeting RAD51; STX200 targeting RAF1; STX300 targeting KRASG122X, STX400 targeting NRas; STX500 targeting Cbl-b and STX600 targeting Shoc2. All are in preclinical development. SyntheX’s investors include BMS, SOSV, OMX/Ventures, MorganNoble, Oriza Ventures and 8VC. The Autolus Therapeutics agreement provides BMS with access to Autolus’ RQR8 safety switch, which BMS can then incorporate into specific cell therapies for cancer indications. Toxic side effects, such as cytokine release syndrome and brain toxicity, are common in cell therapies. In these types of cell therapies, such as CAR-T, T-cells are genetically engineered to respond to specific cancer antigens and their epitopes. They are then infused back into the patient, where they become a living therapy, producing more T-cells to attack the cancer cells. But they can grow too fast or too much, which causes severe side effects. Safety switches, such as Autolus’ RQR8, are a way of limiting these side effects by placing limits on T-cell production. “Safety switches are critical to the future of our field of advanced cell therapies,” said Martin Pule, Autolus’ CSO in a prepared statement. “They allow us to develop approaches that are designed to significantly improve patient outcomes, whilst at the same time incorporating the potential to reduce the risk of severe adverse side effects from the treatment.” Autolus’ proprietary RQR8 switched is administered with Genetech and Biogen’s Rituxan (rituximab). Rituxan is approved to treat non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangiitis and microscopic polyangiitis and pemphigus vulgaris. Once dosed, rituximab binds to the engineered CD20 epitopes on the surface of the cell therapy and triggers selective cell death. RQR8 is a 136-amino-acid epitope-based marker/suicide gene. A suicide gene is genetically coded so that it selectively destroys transferred T cells when facing unacceptable levels of toxicity, a common severe side effect of CAR-T and cell therapies. Specifically, RQR8 is for T-cells and combines target epitopes from both CD34 and CD20 antigens, which allows selection from a clinically approved CliniMACS CD34 system (Miltenyi), a medical device system designed to enrich CD34+ targets. Binding with rituximab, it selectively deletes transgene-expressing cells.