Justin Lim ’26

Figure 1: Breast cancer cells (1).jpg

Cancer, a group of diseases characterized by uncontrolled and abnormal cell growth, is generally recognized by its genomic instability built up by bypassing important biological checkpoints. These checkpoints are scattered throughout a cell’s growth period to limit the amount of DNA replication errors and other deleterious mutations during cell division. Due to the evasion of growth inhibitory signals, cancer cells are often extremely genetically volatile due to the accumulation of mutations from DNA replication errors. Jinal A. Patel and her team at Stony Brook University conducted a study to evaluate the adaptive responses of cancer cells within the replication fork (the splitting of the DNA helix to add complementary DNA strands) to replication stress.

By utilizing auxin-inducible degron (AID) technology, TIMELESS (TIM), a protein involved in increased DNA replication activity, could be “tagged” and degraded with the introduction of the plant hormone auxin. The addition of auxin recruits a complex that ubiquitinates TIM, marking it for degradation by the proteasome. Once TIM degradation occurs, a multitude of markers of replication fork instability increases including elevated levels of pRPA32 S4/S8, pKAP1 S824, and widespread γH2AX signals. By degrading TIM, ATR inhibition also becomes more effective in creating replication damage creating a sort of “synergistic” or multiplicative effect. In other words, TIM degradation and ATR inhibition together create a stronger effect in creating DNA damage stress and therefore cell death than either event happening individually. 

The study’s findings indicate that loss of TIM and ATR inactivation leads to checkpoint activation and is unexpectedly necessary for catastrophic cell death. The group has identified TIM as a point of replication vulnerability in cancer that can be exploited with ATR inhibitors. By leveraging the inherent genomic instability of cancer cells, the degradation of specific proteins, coupled with the inhibition of others, may be used to induce cancer cell death. The study suggests that while these synergistic effects may be reversed through the removal of 5-Ph-IAA and ATRi treatments, the DNA damage incurred during the period is irreparable and will ultimately lead to apoptotic cell death. This synergistic approach to inactivating precise protein complexes or coupling reactions represents a novel strategy in cancer research. It holds promise for personalized therapies that can precisely target the unique genetic characteristics of individual tumors or specific cancer types.

Source: Patel JA, Zezelic C, Rageul J, Saldanha J, Khan A, Kim H. Replisome dysfunction upon inducible TIMELESS degradation synergizes with ATR inhibition to trigger replication catastrophe. Nucleic Acids Res. 2023 Jul 7;51(12):6246-6263. doi: 10.1093/nar/gkad363. PMID: 37144518; PMCID: PMC10325925.

https://doi.org/10.1093/nar/gkad363

Image: https://commons.wikimedia.org/wiki/File:Breast_cancer_cells_(1).jpg