Cyclin D1 is one of the drivers of the cell cycle, and its deregulation may promote the development of tumours. Surprisingly, this protein also mediates the repair of damaged DNA, a mechanism that commonly prevents cancer. See Letter p.230
The maintenance of genome integrity is a fundamental biological process. A complex network of proteins detects damaged DNA, signals this detection and repairs the damage, to prevent life-threatening diseases such as cancer1. This machinery is particularly crucial in cells going through the cell-division cycle, a proliferative process that can go awry in various cancers1,2. But the orchestration of the DNA-damage response and the cell cycle is far from understood, despite the key roles of the two processes in cell physiology and pathology. An exciting report by Jirawatnotai and colleagues in this issue3 (page 230) sheds new light on the matter, identifying an unexpected function for the cell-cycle protein cyclin D1 in DNA repair.
Cyclin proteins drive the cell cycle in partnership with a family of catalytic proteins called cyclin-dependent kinases (CDKs). Various cyclin–CDK complexes fuel the highly regulated progression through the G1, S, G2 and M phases of the cycle by phosphorylating — thereby activating or inactivating — a plethora of cellular proteins. Consistent with their role in cell proliferation, cyclins at abnormally high levels, particularly cyclins D1 and E, contribute to the development of diverse types of cancer2.
To gain further insight into the function of cyclin D1, Jirawatnotai et al.3 purified the protein from several types of human cancer cells and assessed the spectrum of proteins that interact with it. Surprisingly, several of the cyclin-D1 partner proteins turned out to be known components of the DNA-repair machinery. Particularly intriguing was the interaction between cyclin D1 and RAD51, which is a key enzyme involved in homologous recombination — a process that operates in the advanced S and G2 phases of the cell cycle to seal DNA breaks using the intact copy of the DNA sequence as a template1,4. The authors found that cyclin D1 binds to RAD51 directly, and that this interaction is stronger in cells exposed to ionizing radiation3, despite the fact that this genotoxic insult leads to the partial degradation of cyclin D1.
Encouraged by these results, the authors depleted human cells of cyclin D1 and found not only that the cells became more sensitive to DNA-damaging agents such as ionizing radiation or various drugs, but also that they were slower to repair broken DNA and were defective in performing homologous recombination, although not other DNA-repair pathways. Reassuringly, the authors could remedy these defects by re-expressing normal cyclin D1 in such cells. However, a mutant form of the protein that cannot interact with RAD51 was ineffective.
As if the discovery of another function for cyclin D1 wasn't surprising enough, the authors further show that the role of cyclin D1 in DNA repair is independent of its CDK-associated activity3. This clearly separates the classical, CDK-dependent cell-cycle regulatory function of cyclin D1 from its role in DNA repair (Fig. 1). The different roles of cyclin D1 are relevant for cancer biology and treatment. For instance, Jirawatnotai et al. report that the DNA-repair function of this protein is required in cancer cells deficient in a tumour suppressor called retinoblastoma protein — a setting in which the cell-cycle-regulatory activity of cyclin D1 is dispensable5 (Fig. 1).
How does cyclin D1 exert its role in DNA repair at a molecular level? Jirawatnotai et al.3 show that this protein is localized to damaged chromosomal sites, facilitating recruitment of RAD51. They find that cyclin D1 itself is brought to such DNA breaks by BRCA2, another protein that is an established component of homologous recombination (Fig. 1).
Together these findings, which indicate that a core cell-cycle regulator has a non-catalytic function in DNA repair, raise a host of issues, both mechanistic and conceptual. For example, it is unclear how the relatively minor fraction of cyclin D1 that escapes degradation after DNA damage is modified or 'primed' to engage in homologous recombination. This is even more remarkable in the case of cancers involving retinoblastoma deficiency, which are known5 to harbour generally lower levels of cyclin D1. This is not a purely academic issue, because Jirawatnotai and co-workers show that depleting cyclin D1 in retinoblastoma-deficient human tumours grown in mice may sensitize these cancers to radiotherapy. Another question is whether the related cyclins D2 and D3 also participate in the DNA-damage response, especially given that cyclin D1 is not expressed in some cell types.
Mechanistically, it seems unlikely that cyclin D1 is part of the core machinery responsible for homologous recombination. Yeast cells do not have D-type cyclins, and yet they rely on homologous recombination more than do vertebrates4. And the BRCA2-dependent loading of RAD51 at DNA lesions can be reconstituted in a test tube in the absence of cyclin D1.6,7 Therefore, it is more likely that, in vertebrates, cyclin D1 has evolved to facilitate homologous recombination by simultaneously binding RAD51 and BRCA2, and so increasing their local concentration at damaged chromosomes.
Arguably most puzzling is the apparent discrepancy between the tumour-promoting, cell-cycle function of cyclin D1 and its role in DNA repair, which — by analogy with other repair processes1,8 — should help to prevent cancer. Perhaps this conundrum would be resolved if cyclin D1 facilitated DNA repair, and hence survival of cancer cells, in the face of the severe, endogenous, oncogene-induced DNA damage to which the cells are exposed as well as the damage induced by genotoxic therapy1,9. Such a concept is plausible because, like cyclin D1, RAD51 is often expressed at high levels in tumours, and this might promote the fitness of such cancers and potentially increase their resistance to treatment.
Jackson, S. P. & Bartek, J. Nature 461, 1071–1078 (2009).
Sherr, C. J. & Roberts, J. M. Genes Dev. 18, 2699–2711 (2004).
Jirawatnotai, S. et al. Nature 474, 230–234 (2011).
Mazón, G., Mimitou, E. P. & Symington, L. S. Cell 142, 646 (2010).
Bartek, J. et al. Curr. Opin. Cell Biol. 8, 805–814 (1996).
Jensen, R. B., Carreira, A. & Kowalczykowski, S. C. Nature 467, 678–683 (2010).
Thorslund, T. et al. Nature Struct. Mol. Biol. 17, 1263–1265 (2010).
Hoeijmakers, J. H. J. Nature 411, 366–374 (2001).
Halazonetis, T. et al. Science 319, 1352–1355 (2008).
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