New research from Memorial Sloan Kettering Cancer Center (MSK) provides insights into how BRCA2 promotes genomic integrity; illuminates how embryonic cells can develop without key amino acids; explores how the microbiome bounces back after antibiotic treatment; and investigates acquired resistance to immunotherapy in non-small cell lung cancer.
New insights about how BRCA2 promotes genomic integrity
When cells are unable to repair damage to their DNA, it can lead to mutations and the development of cancer. The protein BRCA2 plays an important role in helping cells maintain the integrity of their genomes. This helps explain why people who carry mutations in the BRCA2 gene have an increased likelihood of developing certain cancers, especially breast and ovarian cancers, but also cancers of the prostate and pancreas.
More than 20 years ago, the lab of Maria Jasin, PhD, in the Developmental Biology Program at MSK's Sloan Kettering Institute demonstrated that BRCA2 repairs damage to DNA using a process called homologous recombination, in which the damaged DNA is repaired faithfully by copying from an unrepaired DNA. But since then, the story has become more complicated, as BRCA2 has been shown to participate in two other genome maintenance processes.
A recent study led by Pei Xin Lim, PhD, a senior research scientist in the Jasin lab, used cell lines and mouse models that express a variant of BRCA2 to interrogate the relative importance of the three processes. For this work, he focused on the C-terminal end of BRCA2, which interacts with another protein called RAD51 that forms filaments on DNA. This interaction results in highly stable RAD51 filaments, which is important in protecting replication forks and also suppressing the formation of replication gaps. Dr. Lim found that defective homologous recombination, but not defects in these latter two functions of BRCA2, accelerate tumor formation in mice and increase the sensitivity of cells to a number of drugs, including a class of drugs called PARP inhibitors used in cancer treatment. However, BRCA2 function in the suppression of gaps is important for protecting cells from a potentially new class of drugs resulting in the incorporation of aberrant nucleotides in DNA.
