In this issue, Raso et al. (2020. J. Cell Biol.https://doi.org/10.1083/jcb.202002175) uncover a novel replication fork speed regulatory network controlled by the ubiquitin-like modifier interferon-stimulated gene 15 (ISG15), which plays a central role in the innate immune response and regulates tumorigenesis as well as chemotherapy response

Meroni, Alice

Vindigni, Alessandro

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Washington University School of Medicine Digital Commons@Becker Open Access Publications 2020 ISG15 fast-tracks DNA replication Alice Meroni Alessandro Vindigni Follow this and additional works at: https://digitalcommons.wustl.edu/open_access_pubs SPOTLIGHTISG15 fast-tracks DNA replicationAlice Meroni and Alessandro VindigniIn this issue, Raso et al. (2020. J. Cell Biol. https://doi.org/10.1083/jcb.202002175) uncover a novel replication fork speedregulatory network controlled by the ubiquitin-like modifier interferon-stimulated gene 15 (ISG15), which plays a central role inthe innate immune response and regulates tumorigenesis as well as chemotherapy response.DNA replicates by unzipping its two inter-woven strands and making copies of each.As the DNA strands separate and copy, theyform a “replication fork.” The speed atwhich replication forks progress along theDNA must be tightly controlled to ensuregenome stability and faithful duplication ofthe genome. In this issue, Raso et al. (1)uncover a novel replication fork speed reg-ulatory network controlled by the ubiquitin-like modifier interferon-stimulated gene 15(ISG15). They propose that higher expres-sion of ISG15 induced by interferons orcommonly detected in many types of cancercells drives deregulated fork speed, leadingto DNA damage and genome instability.ISG15 is as ubiquitin-like modifier thatplays a central role in the innate immuneresponse, which is the first line of host de-fense against a vast array of pathogens,including bacteria, fungi, viruses, andparasites. The innate immune responsepromotes the production of interferons(IFNs) that in turn stimulate the productionof ISG15 (2). ISG15 acts by modifying cellularproteins in a process called ISGylation con-sisting on the conjugation of a small-sizepolypeptide similar to ubiquitin to targetproteins. The exact function of ISG15 and itsubiquitin-like activity in the innate immuneresponse is poorly understood. Interestingly,ISG15 is highly expressed in many tumortypes, but how its higher expression levelscorrelate with tumorigenesis and cancer cellresponse to chemotherapeutics remains largelyunexplored.Raso et al. provide a fresh view into thefunction of ISG15 by showing that its higherexpression levels increase replication forkspeed, leading to DNA damage and genomicinstability. The idea that increasing repli-cation fork speed above a certain thresholdleads to DNA damage and genome instabilityis an emerging theme in the replicationfield, whereby faster replicating forks haveinsufficient time to recognize damaged DNAin need of repair. This leads to accumulationof DNA damage and increased cellular sensi-tivity to DNA damaging agents, as observed byRaso et al. A central post-translation modifi-cation for replication speed is poly-(ADP-ribosyl)ation mediated by the PARP family ofproteins, whose inhibition also leads to fasterreplication forks (3). Raso et al. suggest thatPARP inhibitors and ISG15 affect replicationfork speed by similar mechanisms and showthat increasing ISG15 levels significantly en-hances cancer cell sensitivity to PARP in-hibitors. PARP inhibitors are used to treatdifferent tumor types, particularly those car-rying mutations in key DNA repair genes (4).The findings of Raso et al. reveal that theISG15-dependent increase in fork speed is animportant and previously unappreciated mod-ulator of cancer cell response to PARP inhibitorsand DNA-damaging chemotherapy.To uncover the pathway by which ISG15speeds up replication forks, Raso et al. ran amass spectrometry analysis searching forISG15-interacting proteins and found anumber of chromatin-associated factors,some of which were previously reported tointeract with replication forks. Amongthese, they focused on the human RECQ1helicase, a protein that promotes the restartof stalled replication forks (5). In particular,RECQ1 promotes restart by facilitating theresolution of reversed fork structures. Forkreversal is a mechanism that allows repli-cation forks to cope with DNA damage en-countered ahead of their path by reversingtheir course (6). The results of Raso et al.suggest that ISG15 may regulate RECQ1function by unleashing its reversed forkrestart activity. Interestingly, this mecha-nism depends on the functional interactionof ISG15 with the RECQ1 helicase but seemsto be largely independent of ISG15 conju-gation activity. These findings have severalimportant implications. First, they point to apotential and previously unappreciated roleof ISG15 in replication fork reversal, eventhough the exact mechanism by whichISG15 promotes the reversed fork restartfunction of RECQ1 remains elusive. Second,the effect of PARP inhibitors on replicationfork restart also relies on the deregulation ofRECQ1 activity (5), suggesting that ISG15and PARP inhibitors might affect replicationfork progression by a similar mechanism.Third, the authors’ findings point to a novellink between deregulated fork progressioninduced by the ISG15-PARP inhibitor-RECQ1axis, increased DNA damage, and cancer cellresponse to chemotherapy. These findingsalso suggest that increased RECQ1 activitycaused by high ISG15 levels or PARP inhibi-tionmight represent an important vulnerability.............................................................................................................................................................................Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO.Correspondence to Alessandro Vindigni: avindigni@wustl.edu.© 2020Meroni and Vindigni. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–NoMirror Sites license for the first six months afterthe publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).Rockefeller University Press https://doi.org/10.1083/jcb.202007028 1 of 2J. Cell Biol. 2020 Vol. 219 No. 8 e202007028Downloaded from http://rupress.org/jcb/article-pdf/219/8/e202007028/1047544/jcb_202007028.pdf by Washington University In St. Louis Libraries user on 07 November 2020to be exploited in cancer treatment. As in-creased ISG15 levels sensitize cancer cells toDNA damaging chemotherapeutics and PARPinhibitors, monitoring ISG15 or RECQ1 levels intumor samples may represent a novel predic-tive parameter to stratify patients in personal-ized cancer therapy.The innate immune system operatesunder the assumption that no free DNAshould be present in the cytosol and that anycytosolic DNA linked to bacterial or viralinfection is recognized as nonself (7). Cyto-solic DNA can be recognized by the cGAS-STING pathway, which induces type I IFNsand other cytokine genes (8). Recent studiesdemonstrated that, in addition to pathogens,defects in replication fork processing canalso lead to the accumulation of cytosolicDNA and transactivate innate immune re-sponse genes, leading to higher expressionof ISG15 (9). These studies, along with thefindings of Raso et al., suggest that ISG15might be at the center of a feedback loopwhere the increased replication fork speedlinked to higher ISG15 expression leads toincreased replication stress, in turn acti-vating the innate immune response.In summary, Raso et al. provide a freshview on the function of a central immuneresponse factor in genome stability andoutline a previously unknown networkinfluencing replication fork speed (Fig. 1).Their work opens several new areas of in-vestigation that will revolutionize currentmodels of how innate immune responsegenes regulate tumorigenesis and chemo-therapy response, but it also raises severalquestions. For example, the authors’ obser-vation that the ISG15 function in replicationis largely uncoupled from its conjugationactivity begs the question of what might bethe role of this activity in the context of DNAdamage and replication stress. In particular,the mass spectrometry analysis revealedseveral other ISG15 interactors whosefunction might be regulated by ISGylationactivity. A key challenge for future studieswill be to understand if ISG15, and its in-teraction with these protein partners, playadditional roles in genome maintenancebesides the observed regulation of RECQ1’sfork restart function.Another area of interest for future re-search is to explore why cells evolved asystem that is potentially harmful to cellsurvival to counteract host infection. Rasoet al. speculate that the detrimental effectsof ISG15 might arise only when its increasedexpression is uncoupled from its conjuga-tion function, but this would need to bedemonstrated. Finally, the findings of Rasoet al. will no doubt prompt many researchgroups to study why cancer cells choose toincrease ISG15 expression. How does higherISG expression give an advantage to cancercell growth? Recent studies suggest thatISG15 has either oncogenic or tumor-suppressive effects depending on the con-text (10), and the findings of Raso et al. willundoubtedly spark new research to under-stand the connection between deregulatedfork speed caused by higher ISG15 expres-sion and tumorigenesis.AcknowledgmentsThe authors declare no competing financialinterests.References1. Raso, M.C., et al. 2020. J. Cell Biol. https://doi.org/10.1083/jcb.2020021752. Perng, Y.C., and D.J. Lenschow. 2018. Nat. Rev.Microbiol. https://doi.org/10.1038/s41579-018-0020-53. Maya-Mendoza, A., et al. 2018. Nature. https://doi.org/10.1038/s41586-018-0261-54. Ashworth, A., and C.J. Lord. 2018. Nat. Rev.Clin. Oncol. https://doi.org/10.1038/s41571-018-0055-65. Berti, M., et al. 2013. Nat. Struct. Mol. Biol.https://doi.org/10.1038/nsmb.25016. Neelsen, K.J., and M. Lopes. 2015. Nat. Rev.Mol. Cell Biol. https://doi.org/10.1038/nrm39357. Gasser, S., et al. 2017.Mech. Ageing Dev. https://doi.org/10.1016/j.mad.2016.09.0018. Dhanwani, R., et al. 2018. Curr. Opin. Immunol.https://doi.org/10.1016/j.coi.2017.11.0049. Coquel, F., et al. 2018. Nature. https://doi.org/10.1038/s41586-018-0050-110. Han, H.G., et al. 2018. Cancer Lett. https://doi.org/10.1016/j.canlet.2018.09.007Figure 1. The ISG15-RECQ1 network controls replication fork speed.High levels of ISG15 expression,which are triggered by the production of interferons and are commonly detected in many human tumors,stimulate the replication fork start activity of RECQ1, leading to accelerated fork speed and increasedgenomic instability.Meroni and Vindigni Journal of Cell Biology 2 of 2ISG15 fast-tracks DNA replication https://doi.org/10.1083/jcb.202007028Downloaded from http://rupress.org/jcb/article-pdf/219/8/e202007028/1047544/jcb_202007028.pdf by Washington University In St. Louis Libraries user on 07 November 2020

ISG15 fast-tracks DNA replication

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ISG15 fast-tracks DNA replication

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