Homologous recombination is a basic process of life, which is necessary to protect and restart broken replication forks, repair chromosome breaks and exchange genetic material during meiosis. Recently, in a research report titled “Structure and function of the RAD51B-RAD51C-RAD51D-XRCC2 tumor suppressor complex” published in the journal Nature, scientists from institutions such as the Francis Crick Institute summarized the structure and function of a special protein complex, which is crucial for repairing damaged DNA and protecting the body against cancer.
Every time when cells replicate, errors in the form of mutations will occur, but there are special proteins to repair these damaged DNA. Individuals carrying mutations in the DNA repair protein called BRCA2 are more likely to suffer from breast cancer, ovarian cancer, and prostate cancer, which often occur when they are young. Clinically, these cancers are often treated with drugs that inhibit PARP, another protein needed for DNA repair. Recent research results show that defects in a variety of other proteins can also lead to heritable breast cancer, ovarian cancer, or Fanconi anemia, which is a blood disorder that often causes different cancers, including leukemia.
(Luke A Greenhough et al, 2023)
In this article, the researchers revealed the atomic structure of four proteins using Cryo-EM, which together formed a complex called BCDX2, which can urge researchers to draw cancer-related mutations on the 3D structure, reveal the important region of the complex, and clarify why some mutations can prevent DNA repair, thus leading to individual gene instability and cancer occurrence. In addition, researchers also found the role of BCDX2 in cells, and revealed that it may play a role as a “molecular chaperone”, which can target another protein called RAD51, so as to promote its recognition and aggregation in the region where DNA repair is needed. BRCA2, BCDX2, and RAD51 are the main roles in the process of repairing damaged DNA together, which is, homologous recombination.
Researchers suggest that BCDX2 is important in repairing DNA alongside BRCA2, indicating that routine screening for its mutations is necessary. Dr. Luke Greenhough said that “In this study, we have for the first time revealed a direct correlation between structure, function, and why mutations in any component of BCDX2 can lead to cancer.” Now researchers also understand the key role of BCDX2 in DNA repair, and explain why mutations can lead to cancer. Just five years ago, researchers were unable to achieve this, and the rapid development of technology may have made this research possible. DeepMind’s AlphaFold2 (a computer program that can predict the 3D structure of proteins), Cryo-EM technology, and high-resolution imaging technology can enable researchers to obtain a comprehensive view of the structure and function of key protein complexes, which is a very collaborative project, across multiple laboratories and technical teams at the Francis Crick Institute.
This study may help scientists provide the best therapeutic methods for cancer patients. Researchers believe that BRCA2 has very obvious characteristics, and it is known that it can increase the risk of individual cancer, especially breast cancer and ovarian cancer. BRCA2 will mutate in 15% -20% of heritable cancer cases, so scientists need to conduct regular screening for patients. The results of this study show that BCDX2 is critical to DNA repair and will play a role in the same way as BRCA2. For cancer patients induced by BCDX2 deficiency, PARP inhibitors seem to be effective; Researchers believe that individuals with a family history of these cancers should screen for mutations in the BCDX2 protein to gain a more comprehensive understanding of their risk.
At present, researchers hope to elucidate the structure and related information of another protein complex involved in cancer development, called CX3. Putting all this information together may help scientists better understand the genes that put people at risk for cancer and help develop more targeted new therapies. In conclusion, the research results in this paper show that BCDX2 may be able to coordinate RAD51 to assemble from single-stranded DNA, which can be used for the protection of replication forks and the repair of double-strand DNA breaks, and these processes are crucial to avoid the occurrence of tumors.
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Reference
Luke A Greenhough,Chih-Chao Liang,Ondrej Belan, et al. Structure and function of the RAD51B-RAD51C-RAD51D-XRCC2 tumour suppressor complex, Nature (2023). DOI:10.1038/s41586-023-06179-1