Elsevier

Neuroscience

Volume 145, Issue 4, 14 April 2007, Pages 1213-1221
Neuroscience

Role of DNA repair
DNA repair in differentiated cells: Some new answers to old questions

https://doi.org/10.1016/j.neuroscience.2006.07.006Get rights and content

Abstract

Terminally differentiated cells need never replicate their genomes and may therefore dispense with the daunting task of maintaining several repair systems to constantly scan their entire complement of DNA. Obviously, transcribed genes need to be repaired, so that cells can carry out their specialized functions, but dedicated mechanisms such as transcription-coupled repair and differentiation-associated repair can ensure the maintenance of those transcriptionally active domains.

Many groups have studied DNA repair in differentiated cells, often with divergent results, possibly because there are distinct classes of differentiated cells, with unique properties. Thus neurons ought to last for a lifetime, whereas myocytes are backed by precursor cells, while white blood cells like macrophages are constantly being replaced. More importantly, different DNA repair systems can vary in their response to cellular differentiation, possibly depending on whether they can be coupled to transcription.

Nucleotide excision repair (NER) is probably the most versatile DNA repair system and is coupled to transcription. NER was shown to be attenuated by differentiation in several cell types, including neurons. The attenuation occurs only at the global genome level, with transcribed genes still being efficiently repaired. We have determined that this attenuation results from the lack of ubiquitination of a NER factor, most likely owing to differences in phosphorylation of the ubiquitin-activating enzyme E1. Because there is only one E1 in human cells, it is likely that other metabolic pathways are similarly affected, depending on whether they rely on an E2 enzyme which is sensitive to the state of E1 phosphorylation.

Section snippets

Could terminally differentiated cells dispense with DNA repair?

However, as discussed above, cancer is mainly the consequence of DNA damage persisting upon DNA replication. Conceivably, cells that do not divide may not need to bother with repairing the bulk of their genome. Of course, such cells still need to maintain the integrity of the few genes that they are using, but those represent only a few percent of the total DNA mass and may be targeted by dedicated mechanisms.

Transcription-coupled repair (TCR) is such a mechanism. Its molecular details are not

How is global genomic NER downregulated upon differentiation?

NER is a probably the most versatile DNA repair system, in terms of the lesions it can handle: UV-induced dimers, bulky chemical adducts, protein-DNA adducts, intra-strand crosslinks, etc. This versatility probably originates from the fact that NER senses the distortion caused by a lesion in the double helix, rather than the specific lesion itself (Wood, 1999). In accordance with this model, lesions that cause relatively little bend in the DNA, such as the UV-induced cyclobutane pyrimidine

Maintaining proficient repair in transcribed genes: TCR and DAR

One major requirement of our model is that cells that attenuate DNA repair at the global genomic level nevertheless maintain the integrity of active genes, through TCR for instance. As mentioned above, the mechanistic details of TCR are not fully understood, although it is generally accepted that RNA polymerase II serves as a damage sensor: when stalled by a lesion in the transcribed stand of an active gene, it somehow attracts DNA repair enzymes and triggers preferential repair of the

Conclusion

In this brief review, we have seen that terminally differentiated cells occupy a privileged position when it comes to DNA repair. Because they are not expected to ever replicate their genome, they may dispense with the burden of repairing the bulk of it, as long as they maintain the few genes that they are using. This parsimonious strategy may backfire, though, if some unexpected event forces cells to re-enter the cell cycle and attempt to replicate and transcribe a DNA crippled by lesions. We

Acknowledgments

My work on neurons and macrophages was carried out in the laboratory of Professor Philip C. Hanawalt, at Stanford University. I am deeply grateful to Phil for his constant support and advice during the past 9 years, and to all members of the Hanawalt laboratory for their help with various aspects of these projects. I also would like to thank the organizers of the First Genome Dynamics in Neuroscience meeting, for setting up such an interesting and well-organized meeting.

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