A newly discovered protein, structurally similar to a key DNA repair regulator, may be hijacking the cell’s repair machinery and creating a vulnerability that could be exploited by cancer drugs. Every cell in the body suffers thousands of DNA breaks daily. Cells repair these breaks using two main pathways, and choosing the wrong one—especially during development—can cause severe birth defects or fuel cancer. The protein CtIP normally helps direct cells toward the safer homologous recombination (HR) repair pathway. But the researchers have found a CtIP-like protein that, when overproduced in tumours, binds to CtIP and drags it to the wrong part of the nucleus, where it cannot work. This effectively disables the HR pathway, destabilising the genome and potentially driving cancer—but also creating a weakness. If this project succeeds, it could validate the CtIP-like protein as a biomarker to identify which tumours are HR-deficient and therefore susceptible to specific chemotherapies. It may also reveal the protein itself as a target for new anti-cancer drugs. This is fundamental science: understanding how cells decide which repair pathway to use, and how that decision goes wrong in disease. Similar work on DNA repair proteins has already led to drugs like PARP inhibitors, which exploit HR defects in breast and ovarian cancers.
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The DNA in each cell of our bodies, collectively known as the genome, is constantly being subjected to damage. To maintain cellular integrity and prevent the transmission of genetic errors to daughter cells during division, cells rely heavily on DNA repair mechanisms. Two primary pathways are responsible for repairing DNA breaks: non-homologous end-joining (NHEJ) and homologous recombination (HR). The decision to utilize either NHEJ or HR is tightly regulated, as errors in choosing the appropriate pathway can have devastating consequences, particularly during foetal development. Research has shown that trimming the ends of a DNA break is a critical factor in directing the cell to use the HR pathway for repair. This trimming process is conducted by a protein complex composed of four key proteins: Mre11, Rad50, Nbs1 (which together form the MRN complex), and CtIP. Whilst CtIP serves as the master regulator of the MRN complex's DNA trimming activity during repair, it also has independent roles, such as protecting DNA during replication. The mechanism by which the cell determines whether CtIP will function with the MRN complex to repair DNA breaks or independently to protect DNA during replication remains unclear. However, the significance of this regulation is underscored by the fact that inherited mutations in CtIP or components of the MRN complex lead to severe developmental abnormalities in humans. Understanding how these proteins are controlled is crucial for elucidating how unresolved DNA damage impacts cellular health. Recently, we identified an uncharacterized protein that bears structural similarities to CtIP and is highly expressed in various tumour types. Intriguingly, when this CtIP-like protein is overexpressed, it binds to CtIP and mislocalizes it to regions of the nucleus where it cannot function effectively. This mislocalization potentially compromises the cell’s ability to repair DNA by HR. While an HR deficiency can drive the transformation of a healthy cell into a tumour by compromising genome stability, it can also create a genetic vulnerability that can be targeted with certain chemotherapeutic agents. Given this, we hypothesize that tumours with elevated levels of this CtIP-like protein may harbour an HR defect due to impaired CtIP function, creating a potential vulnerability that could be exploited therapeutically. This project aims to investigate how this CtIP-like protein regulates DNA repair and DNA replication and to determine whether its interaction with CtIP is critical for regulating these processes. By characterizing the function of this protein, we hope to determine how its altered expression affects the DNA repair and replicative capacity of tumour cells and their sensitivity to chemotherapy, especially agents known to be effective against HR-deficient cancers. Consequently, one goal of this work is to validate whether the levels of this CtIP-like protein can be used as a biomarker to stratify tumours for targeted therapy. In addition to this, it has been previously shown that small molecules that block CtIP binding to itself can be used disrupt to CtIP-dependent processes and enhance cellular sensitivity to chemotherapeutic drugs. Based on this, it is plausible that a similar approach could be used to inhibit cellular pathways dependent on this CtIP-like protein. Therefore, we believe that this work is also vital for verifying whether this CtIP-like protein is a potential target for anti-cancer drug development.
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