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Investigators from the University of Birmingham have made significant advances in elucidating two vital DNA repair processes that have previously posed challenges to researchers.
The release of two scholarly articles showcases the collaborative efforts of the Department of Cancer and Genomic Sciences along with the School of Biosciences at the University of Birmingham, highlighting progress in understanding the meticulous orchestration of DNA repair mechanisms.
The critical role of DNA repair mechanisms
Cells have evolved sophisticated systems to safeguard their DNA through continuous surveillance and repair protocols. When DNA sustains damage, internal cellular signals are triggered to identify the affected areas and recruit specialized proteins, often referred to as DNA repair “machines,” to address the issues. This tightly regulated repair process is essential to ensure that the appropriate proteins arrive in precise quantities and in a specific order.
Chemotherapy treatments for various cancers frequently induce DNA damage as a tactic to hinder cell replication and curb the uncontrolled proliferation of tumors. Advancements in comprehending the intricate DNA repair processes, including the identification of which proteins are involved and their respective roles, hold the promise of developing more targeted and effective cancer therapies capable of impeding tumor progression.
“These findings enhance our comprehension of how cellular mechanisms effectively repair damaged DNA. Given that many chemotherapeutic approaches aim to inflict DNA damage, this knowledge opens up avenues for improving existing therapies and innovating new ones,” stated Jo Morris, Professor of Molecular Genetics at the University of Birmingham.
Mechanism of repair signal regulation
The first research paper, published in Nature Communications on Monday, April 14, unveils a “twisting switch” that plays a pivotal role in deactivating initial repair signals by modifying protein shapes. The absence of this switch results in persistent activation of repair signals, which can interfere with the orderly sequence of protein arrival and departure at damaged sites, thereby obstructing the DNA repair process.
This significant discovery clarifies a long-debated topic concerning how the DNA repair protein RNF168—known for its propensity to provoke unchecked signaling—is brought to a halt. The study elucidates a four-step mechanism responsible for the removal of RNF168 from chromatin, mitigating the risk of excess DNA damage signals, and also illustrates that in the absence of these regulatory steps, cells exhibit increased sensitivity to radiation exposure.
Mitigating excessive repair signals
The second study, published in Molecular Cell, reveals that a protein previously believed to be functionally negligible in cellular processes, SUMO4, is actually crucial in curbing the overflow of DNA damage signals.
In the absence of SUMO4, cells experience an overabundance of one particular type of signaling, which can disrupt other critical signals and hinder the recruitment of some repair proteins to the damaged area. Consequently, this leads to the failure of DNA repair efforts. The implications of this research are profound, as they challenge prior assumptions regarding the relevance of SUMO4 in cellular function.
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