DNA Damage Response and Cell Cycle Regulation

The DNA damage response (DDR) constitutes a multifaceted network of sensors, transducers and effectors that preserves genome integrity by detecting and repairing lesions arising from endogenous metabolic by-products or exogenous insults such as ionising radiation and chemotherapeutic agents. Central to this system are the apical kinases ATM and ATR, which orchestrate signal cascades leading to activation of downstream checkpoint kinases CHK1 and CHK2, accumulation of γ-H2AX at sites of double-strand breaks (DSBs) and stabilization of the tumour suppressor p53. These events trigger cell cycle arrest at G1/S, intra-S or G2/M boundaries, allowing time for lesion repair via pathways including homologous recombination or non-homologous end joining. If damage is irreparable, cells may undergo senescence or apoptosis, thereby preventing propagation of mutations. Tight coordination between DDR and cell cycle machinery is crucial not only for normal tissue homeostasis but also for therapeutic strategies that exploit checkpoint vulnerabilities in cancer cells, enhancing radiotherapy or chemotherapeutic efficacy while minimising toxicity to healthy cells.

Research from Nature Portfolio

Advances in systems pharmacology have yielded mechanistic models integrating cell cycle progression with DDR signalling to predict optimal dosing schedules for ATR inhibitors combined with ionising radiation. These models, calibrated with in vitro assays of DNA damage markers and validated in mouse xenografts, inform phase I trial design by forecasting tumour response and improving patient stratification. Another study has characterised SFOM-0046, a novel small molecule that induces replication stress and S-phase arrest, leading to γ-H2AX accumulation. This compound preferentially activates ATR–CHK1 in certain cell lines and engages ATM–CHK2 in others, with p53 status modulating cell survival. In vivo efficacy has been demonstrated without overt toxicity, highlighting SFOM-0046 as a promising candidate for targeting homologous recombination-dependent repair in cancer.

DNA Damage Response and Cell Cycle Regulation publication trend

The graph below shows the total number of articles in dna damage response and cell cycle regulation across all publications each year (not limited to Nature Index journals).

Technical terms

DNA damage response (DDR): A cellular network that detects DNA lesions and coordinates repair with cell cycle checkpoints.

Double-strand break (DSB): A form of DNA damage in which both strands of the double helix are severed.

ATM (Ataxia-Telangiectasia Mutated): A protein kinase that senses DSBs and activates downstream repair and checkpoint pathways.

ATR (ATM- and Rad3-related): A protein kinase that primarily responds to replication stress and single-strand DNA regions.

CHK1/CHK2 (Checkpoint kinases): Effector kinases phosphorylated by ATM/ATR to enforce cell cycle arrest.

γ-H2AX: A phosphorylated histone H2A variant that marks sites of DSBs and recruits repair proteins.

p53: A tumour suppressor protein that governs cell cycle arrest, senescence or apoptosis in response to DNA damage.

References

1. The Potential for Targeting G2/M Cell Cycle Checkpoint Kinases in Enhancing the Efficacy of Radiotherapy. Cancers (2024).
2. Regulation of DNA Repair Mechanisms: How the Chromatin Environment Regulates the DNA Damage Response. International Journal of Molecular Sciences (2017).
3. Bridging the gap between in vitro and in vivo: Dose and schedule predictions for the ATR inhibitor AZD6738. Scientific Reports (2015).
4. Investigation of the DNA damage response to SFOM-0046, a new small-molecule drug inducing DNA double-strand breaks. Scientific Reports (2016).
5. A new compound of thiophenylated pyridazinone IMB5043 showing potent antitumor efficacy through ATM-Chk2 pathway. PLOS ONE (2018).