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Researchers from the University of Birmingham have uncovered answers that provide the detail to explain two specific DNA repair processes that have long been in question.

The publication of two papers demonstrates how work led by laboratories from the Department of Cancer and Genomic Sciences, and the School of Biosciences at the University of Birmingham, has made strides in understanding how the repair process is correctly orchestrated.

The importance of understanding DNA repair

Our cells protect their DNA by constantly monitoring and repairing any damage. When DNA is damaged, internal signals activate within the cell to pinpoint the damage and recruit specialized proteins鈥擠NA repair "machines"鈥攖o fix the break. This repair process must be tightly regulated to ensure the correct proteins arrive in the right amounts and in the correct sequence.

Many chemotherapy treatments for cancers work by damaging DNA to stop replication and subsequent uncontrolled growth of tumors. Improvements in the understanding of complex DNA repair processes, such as knowing which proteins are enlisted and their specific roles and functions, have the potential to lead to refinements in future cancer treatments, making them more effective at halting tumor growth.

Jo Morris, Professor of Molecular Genetics, Cancer and Genomic Sciences, University of Birmingham said, "These discoveries help us understand how our cells work to repair damaged DNA correctly. As many chemotherapies work by damaging DNA, the discoveries provide information about new ways that anti-cancer therapies could be enhanced and new ones developed."

Repair signal switch

The first study, published in Nature Communications, identifies a "twisting switch" that helps turn off early repair signals by altering the shape of proteins. Without the switch, repair signals stay active too long, disrupting the correct sequencing of the repair machine's arrival at and exit from the broken site so that DNA repair is blocked.

The discovery of the twisting switch resolves a long-standing question about how the DNA repair protein RNF168, which has a tendency to cause uncontrolled signaling, is switched off. The paper outlines a four-step process that removes RNF168 from chromatin, preventing excessive DNA damage signals and demonstrates that without these steps, cells become hypersensitive to radiation.

Preventing repair signal overload

A second study published in identified that a component previously assumed to have very little function in cells, SUMO4, has a crucial role in helping prevent the DNA damage signal from being overwhelmed.

Without SUMO4, there is an excess of one type of signaling, disrupting other signals and preventing some repair proteins from reaching the damaged site. As a result, DNA repair fails. The significance of this research comes from the way it challenges earlier assumptions about the importance of the SUM04 protein.