The cellular machinery that replicates DNA would soon stall were it poorly maintained. It is vulnerable to gunky buildup—lesions from various endogenous and exogenous sources. Some gunk removal mechanisms are fairly well known. For example, nucleotide excision repair and homologous recombination have been well studied. Less familiar, however, are repair mechanisms that specifically target the protein component of DNA-protein crosslinks (DPCs).

Reactive compounds such as formaldehyde, which are produced as byproducts of cellular reactions, cause the crosslinking of proteins to DNA. Importantly, DPCs are also caused by several anticancer drugs and are extremely toxic as they interfere with essential processes such as DNA replication. Cells need to unwind and separate the DNA double helix in order to copy its genetic information prior to the next round of cell division. DPCs inhibit this process by blocking the way of the unwinding enzyme replicative helicase, thus preventing replication and consequently cell division.

In the laboratory of Prof. Stefan Jentsch, Ph.D., at the Max-Planck-Institute of Biochemistry, scientists have identified the protease Wss1 as a new safeguarding factor that cleaves the protein components of DPCs and thereby enables cells to duplicate their genome. Details of this work appeared July 3 in the journal Cell, in an article entitled, “A DNA-Dependent Protease Involved in DNA-Protein Crosslink Repair.”

In this article, the authors describe how they determined that the metalloprotease Wss1 is crucial for cell survival upon exposure to formaldehyde and topoisomerase 1-dependent DNA damage. “Yeast mutants lacking Wss1 accumulate DPCs and exhibit gross chromosomal rearrangements,” they wrote. “Notably, in vitro assays indicate that substrates such as topoisomerase 1 are processed by the metalloprotease directly and in a DNA-dependent manner.”

In other words, Wss1 has the unique property of cleaving proteins only in the presence of DNA, suggesting that the enzyme is well tailored for its task to remove crosslinks from the genome and thus preserve genome stability. By clearing away DPCs, the Wss1 protease may, the authors speculate, enable the “repair of these unique lesions via downstream canonical DNA repair pathways.”

Because the repair of DNA lesions is essential to prevent cancer formation, it is of crucial importance to understand the underlying cellular mechanisms. The newly identified DNA-protein crosslink-repair pathway is particularly important for rapidly dividing cells. Given the fact that cancer cells divide much faster than the majority of human cells, Wss1 might be an attractive future drug target for cancer therapy.

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