Coverstory

New controller discovered in DNA copying process

When a body cell starts to divide, its DNA must be copied letter by letter. A delicate process, because the correct genetic code is the basis for the new cell to function properly. Researchers at the Erasmus MC Cancer Institute discovered a new mechanism that acts as a kind of director in the DNA copying process.

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The discovery of a new regulator of the process of DNA copying, also known as replication, comes from the laboratory of Dr. Nitika Taneja of the Department of Molecular Genetics. Her group studies the molecular DNA copying machinery of healthy cells and cancer cells.

Forks

They recently discovered a completely new component of the copying machine, Taneja and her colleagues published in the scientific journal Science Advances . A protein code-named SMARCAD1 appears to ensure that the DNA copying process proceeds in an orderly fashion. In more detail, SMARCAD1 controls unhindered progression of the replication forks. Replication forks are the two untangled strands of the DNA helix that are used as templates for the new copy. The smooth running of replication forks is important because if they get stuck, damage can occur in the DNA. And that damage, in turn, can lead to cancer.

Replication forks develop in the process of DNA replication. Replication forks are the two untangled strands of the DNA helix that are used as templates for the new copy.

The researchers already knew SMARCAD1 from its role in repairing damage in the DNA strands, such as breaks. But now it appears to have a completely different role, in the replication process. Taneja: ‘We discovered that after PhD student Calvin Shun Yu Lo made a version of SMARCAD1 that can still repair breaks, but can no longer assist in the replication process. These really turn out to be two completely separate roles of SMARCAD1. Its role in the replication process seems to be more critical as it in fact prevents the breakage of DNA that results from defective replication forks.’

Nitika Taneja (l) and Calvin Shun Yu Lo (r) used a special microscope and software, purchased through the Nefkens Cancer Program, for unbiased quantitative image-based cell cytometry analysis. Photos by Esther Morren.

Tumor cells

The new study also explains the critical role of SMARCAD1 in the DNA copying process of tumor cells. SMARCAD1 becomes essential in this process and thus, helps them grow. Specifically, the researchers looked at tumor cells defective in BRCA1 expression. BRCA1 is known as a breast cancer gene, but also plays a role in DNA replication. Unlike SMARCAD1, the BRCA1 protein does not interfere with running replication forks, but with stalled forks. Taneja: ‘These processes are separate but linked. In tumors in which BRCA no longer works, the functioning of SMARCAD1 at replication forks turns out to be essential for the survival of tumor cells.’

Chemotherapy

Even though their findings are purely fundamental, they might have clinical relevance, Taneja explains. ‘As BRCA-mutated cancer cells can become resistant to regular chemotherapy treatment, this study also highlights a strong potential for using SMARCAD1 as a new therapeutic target for the treatment of tumors that do not respond to chemotherapy.’