Women with certain mutations in BRCA1 (BResat CAncer gene 1) and BRCA2 (BReast CAncer gene 2) have an increased risk of hereditary breast and ovarian cancer.  Since this discovery, these genes, and the proteins they encode, have attracted great scientific attention. And while people who inherit harmful variants in one of these genes have increased risks fir breast and ovarian cancer, they may also have an increase risk for some other cancers. Furthermore, people who have inherited a harmful variant in BRCA1 and BRCA2 also tend to develop cancer at a much younger ages than people who do not have such a variant.

In a new study, researchers from the University of Copenhagen demonstrated that BRCA2 requires a specific enzyme in order to repair DNA damage. The result of this study can pave the way for more targeted treatment options of a group of cancer patients with mutations in BRCA2.

A codebook
Genes may often be seen as a codebook for the way in which the cell’s building blocks – proteins – should be produced. Inheriting a mutation in a gene leads therefor to an error in this codebook, leading to an error in the protein. In turn, this could potentially disrupt the function of the protein and damage the cell.

The BRCA2 protein, which the gene and namesake BRCA2 is encoding, plays a key role in the repair of certain types of DNA damage in cells. And if DNA damage is not repaired, it can lead to cancer.

Research has shown that BRCA2 has a key role in maintaining genomic integrity,  facilitating the repair of toxic DNA double-strand breaks by homologous recombination. In doing so, BRCA2 acts by promoting RAD51 nucleoprotein filament formation on resected single-stranded DNA.  However, scientists did not fully understood how BRCA2 activity is regulated during homologous recombination.

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In the study the the Danish research team, for the first time, demonstrated that BRCA2 requires a specific enzyme called Protein Phosphatase 2A – B56 or PP2AB56 to be able to repair DNA damage.* This so-called household enzyme, a term used for the enzymes that have many different functions in the cell, is a serine/threonine phosphatase essential for mitosis and regulates many biological processes.

“We found that there is an interaction between BRCA2 and the enzyme which is key to the cell’s ability to repair DNA damage. At the same time, we can see that mutations that impair this interaction reduce the ability to repair DNA damage. We made this discovery by studying a part of BRCA2 that no one has previously looked at,” says Postdoc Sara Marie Ambjørn. Ph.D.

“We have tested mutations found in cancer patients that affect the interaction between the enzyme and BRCA2, and we can see that they affect the cells’ response to a substance used in chemotherapy,” she says.

The researchers hope the study may provide important information about potential cancer risk and more targeted treatment for cancer patients who have a mutation in this part of BRCA2.

Targeted treatments
In order to arrive at these results, the researchers introduced various mutated versions of BRCA2 in human cells in the laboratory and investigated their ability to support DNA repair. They found that if they mutated BRCA2 so that the interaction between the enzyme and BRCA2 was interrupted, the cells could no longer repair damaged DNA.

There are a number of studies that have hinted at a role of the enzyme in connection with repair of DNA damage. However, this study from the University of Copenhagen is the first to directly document how it happens.

“We can now state that it is necessary for the enzyme PP2AB56 to interact with BRCA2 in order for DNA damage to be repaired properly and in a healthy manner. We also know that mutations in the enzyme itself are connected to the development of certain types of cancer. This opens up a perspective for studying whether some cancer patients with mutations in the enzyme may benefit from treatments used for cancer patients with BRCA2 mutations,” Ambjørn concluded.

The result can pave the way for cancer patients with a particular group of mutations to receive a more targeted treatment in the future.

Note
* Protein Phosphatase 2A or PP2A is a heterotrimer composed of scaffolding, catalytic, and regulatory subunits. PP2A complexes with B56 subunits are targeted by Shugoshin and BUBR1 to protect centromeric cohesion and stabilize kinetochore-microtubule attachments. The kinetochore attaches chromosomes to spindle microtubules, modulates the stability of these attachments and relays the microtubule-binding status to the spindle assembly checkpoint (SAC), a cell cycle surveillance pathway that delays chromosome segregation in response to unattached kinetochores.[2][3]

Reference
[1] Ambjørn SM, Duxin JP, Hertz EPT, Nasa I, Duro J, Kruse T, Lopez-Mendez B, Rymarczyk B, Cressey LE, van Overeem Hansen T, Kettenbach AN, Oestergaard VH, Lisby M, Nilsson J. A complex of BRCA2 and PP2A-B56 is required for DNA repair by homologous recombination. Nat Commun. 2021 Sep 30;12(1):5748. doi: 10.1038/s41467-021-26079-0. PMID: 34593815. [Article]
[2] Bel Borja L, Soubigou F, Taylor SJP, Fraguas Bringas C, Budrewicz J, Lara-Gonzalez P, Sorensen Turpin CG, Bembenek JN, Cheerambathur DK, Pelisch F. BUB-1 targets PP2A:B56 to regulate chromosome congression during meiosis I in C. elegans oocytes. Elife. 2020 Dec 23;9:e65307. doi: 10.7554/eLife.65307. PMID: 33355089; PMCID: PMC7787666.
[3] Foley EA, Kapoor TM. Microtubule attachment and spindle assembly checkpoint signalling at the kinetochore. Nat Rev Mol Cell Biol. 2013 Jan;14(1):25-37. doi: 10.1038/nrm3494. PMID: 23258294; PMCID: PMC3762224.

Featured image: A doctor examines mammogram snapshot of breast of patient on the monitors. Photo courtesy: © 2016 – 2021 Fotolia/Adobe. Used with permission

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