Aicardi-Goutières syndrome-associated gene SAMHD1 preserves genome integrity by preventing R-loop formation at transcription–replication conflict regions
Autoři:
Kiwon Park aff001; Jeongmin Ryoo aff003; Heena Jeong aff001; Minsu Kim aff001; Sungwon Lee aff001; Sung-Yeon Hwang aff001; Jiyoung Ahn aff004; Doyeon Kim aff002; Hyungseok C. Moon aff005; Daehyun Baek aff002; Kwangsoo Kim aff006; Hye Yoon Park aff005; Kwangseog Ahn aff001
Působiště autorů:
Center for RNA Research, Institute for Basic Science, Seoul, Republic of Korea
aff001; School of Biological Sciences, Seoul National University, Seoul, Republic of Korea
aff002; Department of Hematology, Oncology and Stem Cell transplantation, Comprehensive Cancer center Freiburg, University of Freiburg, Freiburg, Germany
aff003; Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea
aff004; Department of Physics and Astronomy, Seoul National University, Seoul, Republic of Korea
aff005; Transdisciplinary Department of Medicine & Advanced Technology, Seoul National University Hospital, Seoul, Republic of Korea
aff006
Vyšlo v časopise:
Aicardi-Goutières syndrome-associated gene SAMHD1 preserves genome integrity by preventing R-loop formation at transcription–replication conflict regions. PLoS Genet 17(4): e1009523. doi:10.1371/journal.pgen.1009523
Kategorie:
Research Article
doi:
https://doi.org/10.1371/journal.pgen.1009523
Souhrn
The comorbid association of autoimmune diseases with cancers has been a major obstacle to successful anti-cancer treatment. Cancer survival rate decreases significantly in patients with preexisting autoimmunity. However, to date, the molecular and cellular profiles of such comorbidities are poorly understood. We used Aicardi-Goutières syndrome (AGS) as a model autoimmune disease and explored the underlying mechanisms of genome instability in AGS-associated-gene-deficient patient cells. We found that R-loops are highly enriched at transcription-replication conflict regions of the genome in fibroblast of patients bearing SAMHD1 mutation, which is the AGS-associated-gene mutation most frequently reported with tumor and malignancies. In SAMHD1-depleted cells, R-loops accumulated with the concomitant activation of DNA damage responses. Removal of R-loops in SAMHD1 deficiency reduced cellular responses to genome instability. Furthermore, downregulation of SAMHD1 expression is associated with various types of cancer and poor survival rate. Our findings suggest that SAMHD1 functions as a tumor suppressor by resolving R-loops, and thus, SAMHD1 and R-loop may be novel diagnostic markers and targets for patient stratification in anti-cancer therapy.
Klíčová slova:
Colorectal cancer – Cancer genomics – DNA damage – DNA replication – Fibroblasts – Genomics – Lung and intrathoracic tumors – Synthesis phase
Zdroje
1. Yu KH, Kuo CF, Huang LH, Huang WK, See LC. Cancer Risk in Patients With Inflammatory Systemic Autoimmune Rheumatic Diseases: A Nationwide Population-Based Dynamic Cohort Study in Taiwan. Medicine (Baltimore). 2016;95(18):e3540. doi: 10.1097/MD.0000000000003540 27149461
2. Liu J, Blake SJ, Smyth MJ, Teng MW. Improved mouse models to assess tumour immunity and irAEs after combination cancer immunotherapies. Clin Transl Immunology. 2014;3(8):e22. doi: 10.1038/cti.2014.18 25505970
3. Franks AL, Slansky JE. Multiple associations between a broad spectrum of autoimmune diseases, chronic inflammatory diseases and cancer. Anticancer Res. 2012;32(4):1119–36. 22493341
4. Haanen J, Ernstoff MS, Wang Y, Menzies AM, Puzanov I, Grivas P, et al. Autoimmune diseases and immune-checkpoint inhibitors for cancer therapy: review of the literature and personalized risk-based prevention strategy. Ann Oncol. 2020. doi: 10.1016/j.annonc.2020.03.285 32194150
5. Young A, Quandt Z, Bluestone JA. The Balancing Act between Cancer Immunity and Autoimmunity in Response to Immunotherapy. Cancer Immunol Res. 2018;6(12):1445–52. doi: 10.1158/2326-6066.CIR-18-0487 30510057
6. Rice GI, Bond J, Asipu A, Brunette RL, Manfield IW, Carr IM, et al. Mutations involved in Aicardi-Goutieres syndrome implicate SAMHD1 as regulator of the innate immune response. Nat Genet. 2009;41(7):829–32. doi: 10.1038/ng.373 19525956
7. Crow MK. Type I interferon in systemic lupus erythematosus. Curr Top Microbiol Immunol. 2007;316:359–86. doi: 10.1007/978-3-540-71329-6_17 17969456
8. Crow YJ, Rehwinkel J. Aicardi-Goutieres syndrome and related phenotypes: linking nucleic acid metabolism with autoimmunity. Hum Mol Genet. 2009;18(R2):R130–6. doi: 10.1093/hmg/ddp293 19808788
9. Crow YJ, Manel N. Aicardi-Goutieres syndrome and the type I interferonopathies. Nat Rev Immunol. 2015;15(7):429–40. doi: 10.1038/nri3850 26052098
10. Clifford R, Louis T, Robbe P, Ackroyd S, Burns A, Timbs AT, et al. SAMHD1 is mutated recurrently in chronic lymphocytic leukemia and is involved in response to DNA damage. Blood. 2014;123(7):1021–31. doi: 10.1182/blood-2013-04-490847 24335234
11. de Silva S, Wang F, Hake TS, Porcu P, Wong HK, Wu L. Downregulation of SAMHD1 expression correlates with promoter DNA methylation in Sezary syndrome patients. J Invest Dermatol. 2014;134(2):562–5. doi: 10.1038/jid.2013.311 23884314
12. Li M, Zhang D, Zhu M, Shen Y, Wei W, Ying S, et al. Roles of SAMHD1 in antiviral defense, autoimmunity and cancer. Rev Med Virol. 2017;27(4). doi: 10.1002/rmv.1931 28444859
13. Rentoft M, Lindell K, Tran P, Chabes AL, Buckland RJ, Watt DL, et al. Heterozygous colon cancer-associated mutations of SAMHD1 have functional significance. Proc Natl Acad Sci U S A. 2016;113(17):4723–8. doi: 10.1073/pnas.1519128113 27071091
14. Rodero MP, Crow YJ. Type I interferon-mediated monogenic autoinflammation: The type I interferonopathies, a conceptual overview. J Exp Med. 2016;213(12):2527–38. doi: 10.1084/jem.20161596 27821552
15. Beloglazova N, Flick R, Tchigvintsev A, Brown G, Popovic A, Nocek B, et al. Nuclease activity of the human SAMHD1 protein implicated in the Aicardi-Goutieres syndrome and HIV-1 restriction. J Biol Chem. 2013;288(12):8101–10. doi: 10.1074/jbc.M112.431148 23364794
16. Ryoo J, Choi J, Oh C, Kim S, Seo M, Kim SY, et al. The ribonuclease activity of SAMHD1 is required for HIV-1 restriction. Nat Med. 2014;20(8):936–41. doi: 10.1038/nm.3626 25038827
17. Goldstone DC, Ennis-Adeniran V, Hedden JJ, Groom HC, Rice GI, Christodoulou E, et al. HIV-1 restriction factor SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase. Nature. 2011;480(7377):379–82. doi: 10.1038/nature10623 22056990
18. Merati M, Buethe DJ, Cooper KD, Honda KS, Wang H, Gerstenblith MR. Aggressive CD8(+) epidermotropic cutaneous T-cell lymphoma associated with homozygous mutation in SAMHD1. JAAD Case Rep. 2015;1(4):227–9. doi: 10.1016/j.jdcr.2015.05.003 27051737
19. Coquel F, Silva MJ, Techer H, Zadorozhny K, Sharma S, Nieminuszczy J, et al. SAMHD1 acts at stalled replication forks to prevent interferon induction. Nature. 2018;557(7703):57–61. doi: 10.1038/s41586-018-0050-1 29670289
20. Daddacha W, Koyen AE, Bastien AJ, Head PE, Dhere VR, Nabeta GN, et al. SAMHD1 Promotes DNA End Resection to Facilitate DNA Repair by Homologous Recombination. Cell Rep. 2017;20(8):1921–35. doi: 10.1016/j.celrep.2017.08.008 28834754
21. Santos-Pereira JM, Aguilera A. R loops: new modulators of genome dynamics and function. Nat Rev Genet. 2015;16(10):583–97. doi: 10.1038/nrg3961 26370899
22. Aguilera A, Garcia-Muse T. R loops: from transcription byproducts to threats to genome stability. Mol Cell. 2012;46(2):115–24. doi: 10.1016/j.molcel.2012.04.009 22541554
23. Hamperl S, Bocek MJ, Saldivar JC, Swigut T, Cimprich KA. Transcription-Replication Conflict Orientation Modulates R-Loop Levels and Activates Distinct DNA Damage Responses. Cell. 2017;170(4):774–86 e19. doi: 10.1016/j.cell.2017.07.043 28802045
24. Hamperl S, Cimprich KA. Conflict Resolution in the Genome: How Transcription and Replication Make It Work. Cell. 2016;167(6):1455–67. doi: 10.1016/j.cell.2016.09.053 27912056
25. Lim YW, Sanz LA, Xu X, Hartono SR, Chedin F. Genome-wide DNA hypomethylation and RNA:DNA hybrid accumulation in Aicardi-Goutieres syndrome. Elife. 2015;4. doi: 10.7554/eLife.08007 26182405
26. Petryk N, Kahli M, d’Aubenton-Carafa Y, Jaszczyszyn Y, Shen Y, Silvain M, et al. Replication landscape of the human genome. Nat Commun. 2016;7:10208. doi: 10.1038/ncomms10208 26751768
27. Zeman MK, Cimprich KA. Causes and consequences of replication stress. Nat Cell Biol. 2014;16(1):2–9. doi: 10.1038/ncb2897 24366029
28. Andersson R, Refsing Andersen P, Valen E, Core LJ, Bornholdt J, Boyd M, et al. Nuclear stability and transcriptional directionality separate functionally distinct RNA species. Nat Commun. 2014;5:5336. doi: 10.1038/ncomms6336 25387874
29. Gomez-Gonzalez B, Aguilera A. Transcription-mediated replication hindrance: a major driver of genome instability. Genes Dev. 2019;33(15–16):1008–26. doi: 10.1101/gad.324517.119 31123061
30. Garcia-Muse T, Aguilera A. Transcription-replication conflicts: how they occur and how they are resolved. Nat Rev Mol Cell Biol. 2016;17(9):553–63. doi: 10.1038/nrm.2016.88 27435505
31. Meryet-Figuiere M, Alaei-Mahabadi B, Ali MM, Mitra S, Subhash S, Pandey GK, et al. Temporal separation of replication and transcription during S-phase progression. Cell Cycle. 2014;13(20):3241–8. doi: 10.4161/15384101.2014.953876 25485504
32. Amin MA, Varma D. Combining Mitotic Cell Synchronization and High Resolution Confocal Microscopy to Study the Role of Multifunctional Cell Cycle Proteins During Mitosis. J Vis Exp. 2017(130).
33. Lam FC, Kong YW, Huang Q, Vu Han TL, Maffa AD, Kasper EM, et al. BRD4 prevents the accumulation of R-loops and protects against transcription-replication collision events and DNA damage. Nat Commun. 2020;11(1):4083. doi: 10.1038/s41467-020-17503-y 32796829
34. Kretschmer S, Wolf C, Konig N, Staroske W, Guck J, Hausler M, et al. SAMHD1 prevents autoimmunity by maintaining genome stability. Ann Rheum Dis. 2015;74(3):e17. doi: 10.1136/annrheumdis-2013-204845 24445253
35. Crossley MP, Bocek M, Cimprich KA. R-Loops as Cellular Regulators and Genomic Threats. Mol Cell. 2019;73(3):398–411. doi: 10.1016/j.molcel.2019.01.024 30735654
36. Zhang X, Chiang HC, Wang Y, Zhang C, Smith S, Zhao X, et al. Attenuation of RNA polymerase II pausing mitigates BRCA1-associated R-loop accumulation and tumorigenesis. Nat Commun. 2017;8:15908. doi: 10.1038/ncomms15908 28649985
37. Bhatia V, Barroso SI, Garcia-Rubio ML, Tumini E, Herrera-Moyano E, Aguilera A. BRCA2 prevents R-loop accumulation and associates with TREX-2 mRNA export factor PCID2. Nature. 2014;511(7509):362–5. doi: 10.1038/nature13374 24896180
38. Chang EY, Tsai S, Aristizabal MJ, Wells JP, Coulombe Y, Busatto FF, et al. MRE11-RAD50-NBS1 promotes Fanconi Anemia R-loop suppression at transcription-replication conflicts. Nat Commun. 2019;10(1):4265. doi: 10.1038/s41467-019-12271-w 31537797
39. Franzolin E, Coletta S, Ferraro P, Pontarin G, D’Aronco G, Stevanoni M, et al. SAMHD1-deficient fibroblasts from Aicardi-Goutieres Syndrome patients can escape senescence and accumulate mutations. FASEB J. 2020;34(1):631–47. doi: 10.1096/fj.201902508R 31914608
40. Kohnken R, Kodigepalli KM, Wu L. Regulation of deoxynucleotide metabolism in cancer: novel mechanisms and therapeutic implications. Mol Cancer. 2015;14:176. doi: 10.1186/s12943-015-0446-6 26416562
41. Aden K, Bartsch K, Dahl J, Reijns MAM, Esser D, Sheibani-Tezerji R, et al. Epithelial RNase H2 Maintains Genome Integrity and Prevents Intestinal Tumorigenesis in Mice. Gastroenterology. 2019;156(1):145–59 e19. doi: 10.1053/j.gastro.2018.09.047 30273559
42. Dai B, Zhang P, Zhang Y, Pan C, Meng G, Xiao X, et al. RNaseH2A is involved in human gliomagenesis through the regulation of cell proliferation and apoptosis. Oncol Rep. 2016;36(1):173–80. doi: 10.3892/or.2016.4802 27176716
43. Hatchi E, Skourti-Stathaki K, Ventz S, Pinello L, Yen A, Kamieniarz-Gdula K, et al. BRCA1 recruitment to transcriptional pause sites is required for R-loop-driven DNA damage repair. Mol Cell. 2015;57(4):636–47. doi: 10.1016/j.molcel.2015.01.011 25699710
44. Chang EY, Novoa CA, Aristizabal MJ, Coulombe Y, Segovia R, Chaturvedi R, et al. RECQ-like helicases Sgs1 and BLM regulate R-loop-associated genome instability. J Cell Biol. 2017;216(12):3991–4005. doi: 10.1083/jcb.201703168 29042409
45. Sollier J, Stork CT, Garcia-Rubio ML, Paulsen RD, Aguilera A, Cimprich KA. Transcription-coupled nucleotide excision repair factors promote R-loop-induced genome instability. Mol Cell. 2014;56(6):777–85. doi: 10.1016/j.molcel.2014.10.020 25435140
46. Chang EY, Stirling PC. Replication Fork Protection Factors Controlling R-Loop Bypass and Suppression. Genes (Basel). 2017;8(1). doi: 10.3390/genes8010033 28098815
47. Tungler V, Staroske W, Kind B, Dobrick M, Kretschmer S, Schmidt F, et al. Single-stranded nucleic acids promote SAMHD1 complex formation. J Mol Med (Berl). 2013;91(6):759–70. doi: 10.1007/s00109-013-0995-3 23371319
48. Schneider CA, Rasband WS, Eliceiri KW. NIH Image to ImageJ: 25 years of image analysis. Nat Methods. 2012;9(7):671–5. doi: 10.1038/nmeth.2089 22930834
49. Stein SC, Thiart J. TrackNTrace: A simple and extendable open-source framework for developing single-molecule localization and tracking algorithms. Sci Rep. 2016;6:37947. doi: 10.1038/srep37947 27885259
50. Sridhara SC, Carvalho S, Grosso AR, Gallego-Paez LM, Carmo-Fonseca M, de Almeida SF. Transcription dynamics prevent RNA-mediated genomic instability through SRPK2-dependent DDX23 phosphorylation. Cell Rep. 2017;18(2):334–343. doi: 10.1016/j.celrep.2016.12.050 28076779
51. Goldman MJ, Craft B, Hastie M, Repecka K, McDade F, Kamath A, et al. Visualizing and interpreting cancer genomics data via the Xena platform. Nat Biotechnol. 2020. doi: 10.1038/s41587-020-0546-8 32444850
52. Lilljebjorn H, Henningsson R, Hyrenius-Wittsten A, Olsson L, Orsmark-Pietras C, von Palffy S, et al. Identification of ETV6-RUNX1-like and DUX4-rearranged subtypes in paediatric B-cell precursor acute lymphoblastic leukaemia. Nat Commun. 2016;7:11790. doi: 10.1038/ncomms11790 27265895
53. Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15(12):550. doi: 10.1186/s13059-014-0550-8 25516281
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