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• W2024014099 abstract "Future OncologyVol. 7, No. 12 EditorialFree AccessAttenuated nucleotide excision repair leads to mutagenesis in cancer cellsThierry NouspikelThierry NouspikelInstitute for Cancer Studies, University of Sheffield, Sheffield, S10 2RX, UK. Search for more papers by this authorEmail the corresponding author at t.nouspikel@sheffield.ac.ukPublished Online:23 Nov 2011https://doi.org/10.2217/fon.11.110AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail Keywords: ▪ cancerDNA damageDNA repairmutationsquiescent cellsGenomic stability is the result of an equilibrium between DNA damage and DNA repair. Our genome is constantly challenged by endogenous and exogenous DNA damaging agents that produce a variety of lesions; from single base alterations, to pyrimidine dimers, bulky chemical adducts, intra-strand and inter-strand crosslinks, single-strand nicks and double-strand breaks. Fortunately, we have evolved half a dozen DNA repair systems, each capable of tackling a subset of DNA lesions. The most versatile of these systems is probably nucleotide excision repair (NER), which handles UV-induced pyrimidine dimers, a vast array of bulky chemical adducts, crosslinks and even some forms of oxidative damage. There are two reasons for this versatility; first, for global genome repair (GGR), NER enzymes recognize the distortion that a lesion causes in DNA structure, and thus does not need to identify specific lesions [1]; second, lesions located in the transcribed strand of active genes are detected by the fact that they block RNA polymerase II. The stalled polymerase ‘calls for help’ and recruits NER enzymes, thereby serving as a lesion sensor that preferentially targets NER where it is most needed; in active genes [2]. This process, discovered in the 1980s in the Hanawalt laboratory [3], is known as transcription-coupled repair (TCR).The importance of NER for genomic stability is exemplified by xeroderma pigmentosum (XP), a hereditary disease that can be caused by mutations in several genes encoding NER enzymes. XP patients suffer skin anomalies, hypo- or hyper-pigmentation, skin atrophy and, most strikingly, a very high incidence of skin cancer [4]. These symptoms reflect the crucial importance of NER for the repair of UV-induced DNA lesions, as demonstrated by the fact that they are concentrated in sun-exposed areas of the body. XP patients also suffer from a significantly higher risk of internal cancers, mostly of the respiratory and GI tracts, which probably reflects the role of NER in repairing lesions induced by air pollutants and food carcinogens [5]. By contrast, patients who are specifically deficient in TCR suffer from Cockayne syndrome, a completely different disease, essentially developmental and neurodegenerative, but without increased cancer risk [6].Despite its importance, NER displays considerable variations in efficiency among various tissues. For instance, it has long been known that NER is attenuated in terminally differentiated cells such as neurons, myocytes, adipocytes or macrophages [7]. Over 15 years ago, I had the privilege of joining the laboratory of Phil Hanawalt, one of the great pioneers of DNA repair who discovered repair replication – the basic mechanism of NER – in the early 1960s [8]. As a postdoctoral project, Phil suggested that I might investigate the mechanism of NER downregulation in neurons, and try to understand how these cells can survive without maintaining the integrity of their genome. DNA damage potentially impairs two major processes; DNA replication and transcription. Replication is obviously not an issue in postmitotic cells, but lesions that stall RNA polymerase or cause misincorporations in the RNA (a process known as transcriptional mutagenesis [9]) must be equally toxic for dividing and nondividing cells, as demonstrated by the neurological symptoms of Cockayne syndrome patients. I discovered that, in terminally differentiated cells, NER is downregulated at the global genome level, except in active genes where both strands remain proficiently repaired [10].The latter finding was particularly important, because it meant that proficient repair could not be explained solely by TCR, which only targets the transcribed strand, since lesions in the nontranscribed strand do not stall RNA polymerases [11]. By contrast, both strands were repaired in terminally differentiated cells, a phenomenon I named transcription domain-associated repair (DAR). We later obtained genetic and molecular evidence that DAR is simply a concentration of the remaining NER activity in subnuclear ‘transcription factories’, thereby providing a repair-proficient environment for transcribed genes in cells that are otherwise GGR deficient [12].The mechanism underlying the downregulation of GGR took more time to elucidate and we are still working out its details in my laboratory. In brief, we found that, in actively replicating cells, proficient NER requires the ubiquitination of one of its components; most likely the TFIIH complex. This activation process is reduced in terminally differentiated cells, likely owing to a decrease in phosphorylation of the ubiquitin-activating enzyme, Ube1 [13]. Incidentally, the latter constitutes a fairly unusual regulatory mechanism, as the regulation of ubiquitination generally occurs at the level of the E3 enzyme [14]. Since TFIIH is also a general transcription factor, the remnants of correctly ubiquitinated TFIIH might be concentrated in transcription factories, thereby explaining DAR [14].One might wonder why nature bothered to implement such a mechanism, and downregulate NER in noncycling cells. The teleological explanation is that terminally differentiated cells never need to replicate their genome, and thus have no reason to spend the energy required to maintain the bulk of it when they can concentrate their efforts on the only portion that matters for them; transcribed genes. However, this strategy may backfire if for some reason these cells attempt to re-enter the cell cycle. We have hypothesized that it may be one of the causes of neurodegeneration in Alzheimer’s disease. It is now well accepted that, in Alzheimer’s disease and other neurodegenerative diseases, neurons attempt to resume the cell cycle, and even replicate their DNA, but fail to divide and die for unknown reasons [15]. We have proposed that one reason could be that they attempt to replicate and transcribe a genome that has been left in disrepair for many years, and likely accumulated a large number of lesions [16].More recently, we considered a more common case; that of temporarily quiescent cells. Cells such as hepatocytes, muscle satellite cells and B lymphocytes do not normally divide, but retain the ability to resume proliferation if circumstances demand it. One would expect that NER shall remain proficient in these cells, as genome integrity will be a critical requirement when proliferation resumes. Yet, when we looked at quiescent human B lymphocytes, we found the very same downregulation of NER that we had observed in terminally differentiated cells, proceeding from the same mechanism [17].The consequences of such an attenuation in DNA repair are obviously much more severe for lymphocytes than for neurons. When B lymphocytes are stimulated to proliferate, for example by an infection, they will replicate a genome that has not been repaired for many weeks. Lesions that stall replication forks can nevertheless be bypassed by recruiting specialized ‘translesion’ polymerases, which have the ability to replicate a damaged template before handing it back to replicative polymerases. The price to pay, however, is higher mutagenesis; as translesion polymerases typically have low fidelity [18]. Thus, mutations acquired during replication across unrepaired DNA lesions explain the high incidence of cancer in the rapidly proliferating epithelial cells of XP patients. We have verified that it is also the case for B lymphocytes obtained from normal donors, in which we have observed a high rate of mutagenesis (similar to that of XP cells) in several genes, including one of the most commonly mutated genes in B lymphoma, BCL6[17].I believe this unfortunate situation is not unique to B lymphocytes and that NER downregulation might be a common feature of noncycling cells, whether terminally differentiated, senescent or temporarily quiescent. In the latter case, resumed replication results in high mutagenesis, leading to increased risk of a carcinogenic transformation. This may even be an explanation for the emergence of cancer stem cells [19]. These elusive, mostly quiescent cells are believed to constitute the ‘beating heart’ of many tumors, to be resistant to therapy during their quiescent phase and to constantly spawn a population of fast-dividing, active cancer cells. The origin of cancer stem cells is still debated but one prominent theory is that they derive from adult stem cells that, for some reason, became cancerous [20]. If NER is indeed downregulated in quiescent adult stem cells, these would accumulate mutations by the same mechanism we described for lymphocytes, which may explain their transformation.In conclusion, it is well established that a complete lack of NER results in high cancer propensity in proliferating tissues, in which replication of damaged DNA leads to high mutagenesis. Specific defects in TCR do not cause cancer, since all lesions are eventually repaired by GGR, but the impairment in transcription caused by this belated repair may result in cell death, and cause symptoms such as neurodegeneracy.I am arguing here that a physiological, tissue-specific attenuation of NER places some cell types at a risk of carcinogenic transformation. While NER might be safely confined to transcribed genes in terminally differentiated cells, the same downregulation mechanism causes high mutagenesis in temporarily quiescent cells when they resume replication.My hope is that, once we have worked out the details of this mechanism, we can take control of it and activate or attenuate NER in a tissue-specific manner for preventive or therapeutic purposes. For instance, downregulating NER in rapidly replicating cells (namely cancer cells) would likely render them highly sensitive to most DNA-damaging chemotherapeutic agents, while having little side effects on the vast majority of quiescent cells in our body, in which NER is already attenuated.Financial & competing interests disclosureThe work described here was supported by grants from the Swiss National Science Foundation (823-046695), the Novartis Jubilaum Stiftung, the Ellison Medical Foundation (AG-SS-0555-00), the US National Cancer Institute (CA44349 and CA77712), Yorkshire Cancer Research, Leukaemia and Lymphoma Research UK (06049) and the UK Biotechnology and Biological Sciences Research Council (BB/E006590/1). The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.References1 Gillet LC, Scharer OD. Molecular mechanisms of mammalian global genome nucleotide excision repair. Chem. Rev.106(2),253–276 (2006).Crossref, Medline, CAS, Google Scholar2 Hanawalt PC. Subpathways of nucleotide excision repair and their regulation. Oncogene21(58),8949–8956 (2002).Crossref, Medline, CAS, Google Scholar3 Bohr VA, Smith CA, Okumoto DS, Hanawalt PC. DNA repair in an active gene: removal of pyrimidine dimers from the DHFR gene of CHO cells is much more efficient than in the genome overall. Cell40(2),359–369 (1985).Crossref, Medline, CAS, Google Scholar4 Kraemer KH, Lee MM, Scotto J. Xeroderma pigmentosum. Cutaneous, ocular, and neurological abnormalities in 830 published cases. Arch. Dermatol.123,241–250 (1987).Crossref, Medline, CAS, Google Scholar5 Kraemer KH, Lee MM, Scotto J. DNA repair protects against cutaneous and internal neoplasia: evidence from xeroderma pigmentosum. Carcinogenesis5(4),511–514 (1984).Crossref, Medline, CAS, Google Scholar6 Nance MA, Berry SA. Cockayne syndrome: review of 140 cases. Am. J. Med. Genet.42,68–84 (1992).Crossref, Medline, CAS, Google Scholar7 Nouspikel T. DNA repair in differentiated cells: some new answers to old questions. Neuroscience145,1213–1221 (2007).Crossref, Medline, CAS, Google Scholar8 Pettijohn D, Hanawalt P. Evidence for repair-replication of ultraviolet damaged DNA in bacteria. J. Mol. Biol.9,395–410 (1964).Crossref, Medline, CAS, Google Scholar9 Saxowsky TT, Doetsch PW. RNA polymerase encounters with DNA damage: transcription-coupled repair or transcriptional mutagenesis? Chem. Rev.106(2),474–488 (2006).Crossref, Medline, CAS, Google Scholar10 Nouspikel T, Hanawalt PC. Terminally differentiated human neurons repair transcribed genes but display attenuated global DNA repair and modulation of repair gene expression. Mol. Cell Biol.20,1562–1570 (2000).Crossref, Medline, CAS, Google Scholar11 Mellon I, Spivak G, Hanawalt PC. Selective removal of transcription-blocking DNA damage from the transcribed strand of the mammalian DHFR gene. Cell51(2),241–249 (1987).Crossref, Medline, CAS, Google Scholar12 Nouspikel T, Hyka-Nouspikel N, Hanawalt PC. Transcription domain-associated repair in human cells. Mol. Cell Biol.26(23),8722–8730 (2006).Crossref, Medline, CAS, Google Scholar13 Nouspikel T, Hanawalt PC. Impaired nucleotide excision repair upon macrophage differentiation is corrected by E1 ubiquitin-activating enzyme. Proc. Natl Acad. Sci. USA103(44),16188–16193 (2006).Crossref, Medline, CAS, Google Scholar14 Nouspikel T. Multiple roles of ubiquitination in the control of nucleotide excision repair. Mech. Ageing Dev.132,355–365 (2011).Crossref, Medline, CAS, Google Scholar15 Yang Y, Geldmacher DS, Herrup K. DNA replication precedes neuronal cell death in Alzheimer’s disease. J. Neurosci.21(8),2661–2668 (2001).Crossref, Medline, CAS, Google Scholar16 Nouspikel T, Hanawalt PC. When parsimony backfires: neglecting DNA repair may doom neurons in Alzheimer’s disease. BioEssays25(2),168–173 (2003).Crossref, Medline, CAS, Google Scholar17 Hyka-Nouspikel N, Lemonidis K, Lu WT, Nouspikel T. Circulating human B lymphocytes are deficient in nucleotide excision repair and accumulate mutations upon proliferation. Blood117(23),6277–6286 (2011).Crossref, Medline, CAS, Google Scholar18 McCulloch SD, Kunkel TA. The fidelity of DNA synthesis by eukaryotic replicative and translesion synthesis polymerases. Cell Res.18(1),148–161 (2008).Crossref, Medline, CAS, Google Scholar19 Hyka-Nouspikel N, Nouspikel T. Nucleotide excision repair and B lymphoma: somatic hypermutation is not the only culprit. Cell Cycle10(14),2276–2280 (2011).Crossref, Medline, CAS, Google Scholar20 Passegue E, Jamieson CH, Ailles LE, Weissman IL. Normal and leukemic hematopoiesis: are leukemias a stem cell disorder or a reacquisition of stem cell characteristics? Proc. Natl Acad. Sci. USA100(Suppl. 1),11842–11849 (2003).Crossref, Medline, CAS, Google ScholarFiguresReferencesRelatedDetails Vol. 7, No. 12 eToC Sign up Follow us on social media for the latest updates Metrics History Published online 23 November 2011 Published in print December 2011 Information© Future Medicine LtdKeywords ▪ cancerDNA damageDNA repairmutationsquiescent cellsFinancial & competing interests disclosureThe work described here was supported by grants from the Swiss National Science Foundation (823-046695), the Novartis Jubilaum Stiftung, the Ellison Medical Foundation (AG-SS-0555-00), the US National Cancer Institute (CA44349 and CA77712), Yorkshire Cancer Research, Leukaemia and Lymphoma Research UK (06049) and the UK Biotechnology and Biological Sciences Research Council (BB/E006590/1). The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.PDF download" @default.
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