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DNA damage checkpoints in stem cells, ageing and cancer

Nature Reviews Molecular Cell Biology volume 13, pages 579–590 (2012)Cite this article

Subjects

Key Points

  • Checkpoint responses have diverse roles in adult stem cells depending on the genetic context and the level of DNA damage in tissues and stem cells, which increases with age. Thus, the role of checkpoints in stem cells may change during ageing.

  • The activation of checkpoint genes in response to DNA damage accumulation leads to depletion of stem cells by induction of apoptosis or differentiation. Whether checkpoints induce stem cell senescence remains unclear.

  • DNA damage checkpoint genes influence the maintenance and functionality of undamaged stem cells in adult tissues by controlling self-renewal, quiescence and differentiation. The functions of checkpoint genes in undamaged stem cells seem to be independent of and sometimes contrasting to their roles in DNA damage responses.

  • The deletion of checkpoint genes can lead to defects in quiescence and premature exhaustion of stem cells or to enhanced self-renewal and transformation of stem cells.

  • The deletion of checkpoint responses improves stem cell maintenance in the context of high levels of DNA damage. This can also result in improved tissue maintenance, when chromosomal stability is maintained at the stem cell level. In addition, checkpoint deletion can impair tumour initiation and maintenance by fuelling damage accumulation in cancer stem cells.

  • An increase in the gene dosage of naturally regulated checkpoint genes can lead to improved clearance of molecular damages, prolonged tissue maintenance and decreased carcinogenesis in the context of low levels of DNA damage. Whether these effects are stem cell-dependent is not known.

Abstract

DNA damage induces cell-intrinsic checkpoints, including p53 and retinoblastoma (RB), as well as upstream regulators (exonuclease 1 (EXO1), ataxia telangiectasia mutated (ATM), ATR, p16INK4a and p19ARF) and downstream targets (p21, PUMA (p53 upregulated modulator of apoptosis) and sestrins). Clearance of damaged cells by cell-intrinsic checkpoints suppresses carcinogenesis but as a downside may impair stem cell and tissue maintenance during ageing. Modulating the activity of DNA damage checkpoints can either accelerate or decelerate tissue ageing and age-related carcinogenesis. The outcome depends on cell-intrinsic and cell-extrinsic mechanisms that regulate the clearance of damaged cells and on the molecular context in ageing tissues, including the level of DNA damage accumulation itself.

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Figure 1: Possible mechanisms inducing clonal drifts in stem cell populations in response to DNA damage.
Figure 2: DNA damage checkpoints influence self-renewal, quiescence and maintenance of non-transformed somatic stem cells.
Figure 3: Deletions of checkpoint genes influence DNA damage-induced impairment of somatic stem cells.
Figure 4: Activation or inactivation of DNA damage checkpoints can have positive effects on ageing and cancer depending on the level of DNA damage.

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Acknowledgements

K.L.R. is funded by the Deutsche Forschungsgemeinschaft (DFG; Gottfried-Wilhelm Leibniz Award: Ru745-11, Ru745-10, SPP1356) and the Baden-Württemberg Stiftung (ASII-12 PL Rudolph). The authors apologize for work not being mentioned owing to space restrictions.

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  1. Tobias Sperka and Jianwei Wang: These authors contibuted equally to this work.

Authors and Affiliations

  1. Leibniz Institute for Age Research - Fritz Lipmann Institute (FLI), Beutenbergstr. 11, 07745, Jena, Germany

    Tobias Sperka, Jianwei Wang & K. Lenhard Rudolph

  2. Institute for Molecular Medicine, Ulm University, Germany

    Tobias Sperka, Jianwei Wang & K. Lenhard Rudolph

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  1. Tobias Sperka
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Correspondence to K. Lenhard Rudolph.

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Glossary

Replicative senescence

Terminal cell cycle arrest that limits the number of replication cycles, thus protecting the genomic integrity of a cell from telomere attrition.

Stem cell self-renewal

The capacity to recreate stem cells with the same capabilities resulting from asymmetric (yielding stem cell and progenitor cell) or symmetric cell division (yielding two stem cells). Alternativley, stem cells differentiate, which induces stem cell loss.

Cytokines

Biologically active molecules that are released by cells and affect the function of other cells.

Quiescence

A non-cycling, resting state in the G0 phase of the cell cycle that is important for long-term function.

Autophagy

A catabolic process involving the engulfment of (usually damaged) organelles and long-lived proteins or protein aggregates by autophagosomes, which are double-membrane vesicles. Autophagosomes fuse with lysosomes to form autophagolysosomes, in which their contents are degraded by acidic lysosomal hydrolases.

Mammalian target or rapamycin

(mTOR). A conserved Ser/Thr protein kinase that regulates cell growth, metabolism and the expression of cytokines and growth factors in response to environmental cues.

Tumour stem cells

A small cell population inside a tumour that produces all cell types found in a particular cancer. Tumour stem cells possess stem cell-like traits, including quiescence and self-renewal, rendering them more resistant to elimination compared with the bulk population of stem cells.

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Sperka, T., Wang, J. & Rudolph, K. DNA damage checkpoints in stem cells, ageing and cancer. Nat Rev Mol Cell Biol 13, 579–590 (2012). https://doi.org/10.1038/nrm3420

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