BRCA1/2 MUTATIONS: WHY DO THEY CAUSE CANCER?

Some genes are like the Joe of the group, very well-known. The BRCA genes are such notorious Joes when it comes to breast and ovarian cancers, so well known that even people out of life science careers are aware. But why are these genes infamous for causing cancer? People often mistake that the presence of these genes can cause cancer, nothing could be farther from the truth. These genes are one of the most important caretakers of the genome and when they get mutated, they lose their abilities, making the cell tumorigenic. Mutations in BRCA1 and BRCA2 are associated with breast, ovarian, prostate, pancreas, and other cancers.

The BRCA genes mediate a major pathway called the Homology-Directed repair (HDR) of Double-Strand Breaks (DSBs). DSBs are considered the most lethal forms of DNA Damage that can occur due to exposure to physical, chemical, or biological carcinogens, or even due to stalled replication forks. 

There are two major pathways to repair these DSBs, HDR and Non-Homologous End Joining (NHEJ). Apart from these, some uncertain pathways such as Micro-Homology mediated end joining (MMEJ) and Single Strand Annealing (SSA) also exist. Our stars of the show, the BRCA genes are primarily involved in HDR. HDR is the most accurate DNA repair mechanism that uses the homologous pair of the broken gene as a template to fill in the DSB site, Therefore, mutations in the BRCA1/2 genes disrupt HDR which ultimately leads to lethal mutations, chromosomal rearrangement, and genome instability. Meanwhile, NHEJ non-specifically joins the broken ends of DNA.

HDR’s mechanism involves sequential processes that astutely lead to the repair of the DSB. The first step is to create single-stranded tails at the DSB site, the BRCA1 protein aids this process. This process is termed as “end resection”. This is usually thought of as the BRCA1 protein’s most important role, however, BRCA1 has a much more vital role i.e. it counteracts the NHEJ factor 53BP1 to facilitate the end resection. BRCA1 then interacts with PALB2 protein which in turn recruits BRCA2 and RAD51. RAD51 is the ultimate seeker that finds the homologous pair of the broken DNA. 

The biochemical role of BRCA2 is to enable the RAD51-ssDNA filament formation. This formation is facilitated by BRCA2 by first weakening the binding between RPA (a protein that binds to ssDNA with high affinity) to make room for RAD51 and then guiding RAD51 to bind preferentially to ssDNA rather than dsDNA. BRCA2 promotes a sequential and productive RAD51 filament formation which is key for strand invasion. 

Mutations in BRCA1 are almost completely substituted by suppressing the expression of 53BP1 (or loss) leading to full restoration of HDR except for some roles such as interstrand crosslink repair and replication fork stabilization. Whereas mutations in BRCA2 are a little more complicated to be substituted. BRCA2 is also tethered to other essential pathways that have an impact on genome stability such as G2/M checkpoint maintenance,  R-loop processing, the spindle assembly checkpoint, and cytokinesis. 

Besides the above-mentioned roles, the BRCA1 and BRCA2 along with the FA (Fanconi anemia) proteins are the protectors of the replication fork. This role of theirs is genetically separable from HDR. When a replication fork is stalled due to replication stress, these proteins make sure that the newly synthesized DNA strands aren’t degraded by the MRE11 nuclease. Thus these proteins not only repair the damages that occur in the DNA but also help prevent them. 

The advent of targeted therapies, such as PARP inhibitors, has revolutionized treatment strategies for BRCA-deficient cancers, exemplifying the power of precision medicine. However, challenges remain, including resistance to these therapies and the need for improved diagnostic and preventive measures. As research continues, a deeper understanding of BRCA1/2 and its interactions with other pathways may pave the way for novel interventions, offering hope for those carrying these mutations.

Ultimately, the story of BRCA genes underscores the delicate balance of cellular processes that safeguard life and highlights the importance of early detection, genetic counseling, and continued research in reducing the burden of hereditary cancers.

REFERENCE

Chen CC, Feng W, Lim PX, Kass EM, Jasin M. Homology-Directed Repair and the Role of BRCA1, BRCA2, and Related Proteins in Genome Integrity and Cancer. Annu Rev Cancer Biol. 2018;2:313–36. doi:10.1146/annurev-cancerbio-030617-050502.

CREDITS

Cover Image: https://www.sciencealert.com/cancer