DNA Damage Response in Stem Cell Systems

Stem cells employ a robust and multifaceted DNA damage response (DDR) to preserve genome integrity during rapid proliferation and differentiation. Central pathways include sensing and signalling kinases such as ATM and ATR, which detect double-strand breaks (DSBs) and replication stress, respectively, and activate checkpoints to delay cell cycle progression. Homologous recombination (HR) predominates in pluripotent stem cells, ensuring high-fidelity repair during S and G2 phases, whereas non-homologous end joining (NHEJ) contributes to repair in more differentiated lineages. Chromatin modifiers and reader proteins orchestrate local accessibility, coordinating recruitment of repair complexes to damaged loci. Effective DDR in stem cells underpins developmental fidelity, limits somatic mosaicism and guards against oncogenic transformation. Conversely, aberrations in these pathways can compromise self-renewal, provoke apoptosis or senescence, and contribute to disease. Across embryonic, neural and cancer stem cell populations, interplay between cell-intrinsic factors and extracellular signals modulates DDR efficiency, highlighting both the biological significance and therapeutic potential of targeting repair mechanisms in regenerative medicine and oncology.

Research from Nature Portfolio

Recent studies have revealed that key developmental morphogens converge to regulate replication stress in pluripotent stem cells. Signals such as WNT and BMP restrain excessive origin firing during S-phase, thereby reducing DNA damage and ensuring accurate chromosome segregation. As lineages commit to the three germ layers, protective signalling diminishes but is re-established in neural progenitors by neurogenic factors like FGF2, suggesting a dynamic link between cell identity and genome maintenance that may underlie tissue-specific mosaicism in the developing brain.

Investigations into chromatin ‘reader’ proteins have identified a critical role for a PHD-Bromo domain-containing factor in embryonic stem cells. This reader recognises specific histone modifications, recruits a deacetylase to modulate H3K56 acetylation and facilitates efficient DDR initiation. Loss of this factor leads to elevated DNA damage and genomic instability in pre-implantation blastocysts, underlining the importance of histone-mediated regulation for stem cell genome protection.

DNA Damage Response in Stem Cell Systems publication trend

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

Technical terms

DNA damage response (DDR): A network of sensors, transducers and effectors that detect DNA lesions, signal their presence and coordinate repair, cell cycle arrest or apoptosis.

Double-strand break (DSB): A form of DNA damage where both strands of the double helix are severed, requiring complex repair mechanisms to restore genome integrity.

Homologous recombination (HR): A high-fidelity DSB repair pathway that uses a homologous DNA template, typically favoured during S/G2 phases in proliferating cells.

Non-homologous end joining (NHEJ): A repair mechanism that directly ligates broken DNA ends without the need for extensive homology, often active throughout the cell cycle.

Replication stress: Conditions that impede DNA replication fork progression, leading to ssDNA accumulation, fork remodelling and potential DNA breaks.

Pluripotency: The capacity of a stem cell to self-renew and differentiate into all cell lineages of the embryo, associated with unique cell cycle and repair characteristics.

References

1. Developmental signals control chromosome segregation fidelity during pluripotency and neurogenesis by modulating replicative stress. Nature Communications (2024).
2. Transcriptome Analysis by RNA Sequencing of Mouse Embryonic Stem Cells Stocked on International Space Station for 1584 Days in Frozen State after Culture on the Ground. International Journal of Molecular Sciences (2024).
3. DNA Repair and Therapeutic Strategies in Cancer Stem Cells. Cancers (2023).
4. A short G1 phase imposes constitutive replication stress and fork remodelling in mouse embryonic stem cells. Nature Communications (2016).
5. Maintenance of genome integrity and active homologous recombination in embryonic stem cells. Experimental & Molecular Medicine (2020).
6. TRIM66 reads unmodified H3R2K4 and H3K56ac to respond to DNA damage in embryonic stem cells. Nature Communications (2019).