PARI (PARPBP) suppresses replication stress-induced myeloid differentiation in leukemia cells

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Abstract

Hyperproliferative cancer cells face increased replication stress, which can result in accumulation of DNA damage. As DNA damage can arrest proliferation, and, in the case of myeloid leukemia, induce differentiation of cancer cells, understanding the mechanisms that regulate the replication stress response is paramount. Here, we show that PARI, a replisome protein involved in regulating DNA repair and replication stress, suppresses differentiation of myeloid leukemia cells. We show that PARI is overexpressed in myeloid leukemia cells, and its knockdown reduces leukemia cell proliferation in vitro and in vivo in xenograft mouse models. PARI depletion enhances replication stress and DNA-damage accumulation, coupled with increased myeloid differentiation. Mechanistically, we show that PARI inhibits activation of the NF-κB pathway, which can initiate p21-mediated differentiation and proliferation arrest. Finally, we show that PARI expression negatively correlates with expression of differentiation markers in clinical myeloid leukemia samples, suggesting that targeting PARI may restore differentiation ability of leukemia cells and antagonize their proliferation.

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References

  1. 1.

    Fey MF. Normal and malignant hematopoiesis. Ann Oncol. 2007;18(Suppl 1):i9–i13.

  2. 2.

    Talati C, Sweet K. Recently approved therapies in acute myeloid leukemia: a complex treatment landscape. Leuk Res. 2018;73:58–66.

  3. 3.

    Bruserud O, Gjertsen BT, Huang T. Induction of differentiation and apoptosis: a possible strategy in the treatment of adult acute myelogenous leukemia. Oncologist. 2000;5:454–62.

  4. 4.

    Watts JM, Tallman MS. Acute promyelocytic leukemia: what is the new standard of care? Blood Rev. 2014;28:205–12.

  5. 5.

    de The H. Differentiation therapy revisited. Nat Rev Cancer. 2018;18:117–27.

  6. 6.

    Santos MA, Faryabi RB, Ergen AV, Day AM, Malhowski A, Canela A, et al. DNA-damage-induced differentiation of leukaemic cells as an anti-cancer barrier. Nature. 2014;514:107–11.

  7. 7.

    el-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, et al. WAF1, a potential mediator of p53 tumor suppression. Cell. 1993;75:817–25.

  8. 8.

    Georgakilas AG, Martin OA, Bonner WM. p21: a two-faced genome guardian. Trends Mol Med. 2017;23:310–9.

  9. 9.

    Cheung KJ, Horsman DE, Gascoyne RD. The significance of TP53 in lymphoid malignancies: mutation prevalence, regulation, prognostic impact and potential as a therapeutic target. Br J Haematol. 2009;146:257–69.

  10. 10.

    Hou HA, Chou WC, Kuo YY, Liu CY, Lin LI, Tseng MH, et al. TP53 mutations in de novo acute myeloid leukemia patients: longitudinal follow-ups show the mutation is stable during disease evolution. Blood Cancer J. 2015;5:e331.

  11. 11.

    Melo MB, Ahmad NN, Lima CS, Pagnano KB, Bordin S, Lorand-Metze I, et al. Mutations in the p53 gene in acute myeloid leukemia patients correlate with poor prognosis. Hematology. 2002;7:13–19.

  12. 12.

    Nicolae CM, O'Connor MJ, Constantin D, Moldovan GL. NFkappaB regulates p21 expression and controls DNA damage-induced leukemic differentiation. Oncogene. 2018;37:3647–56.

  13. 13.

    Huang TT, Feinberg SL, Suryanarayanan S, Miyamoto S. The zinc finger domain of NEMO is selectively required for NF-kappa B activation by UV radiation and topoisomerase inhibitors. Mol Cell Biol. 2002;22:5813–25.

  14. 14.

    Huang TT, Miyamoto S. Postrepression activation of NF-kappaB requires the amino-terminal nuclear export signal specific to IkappaBalpha. Mol Cell Biol. 2001;21:4737–47.

  15. 15.

    Huang TT, Wuerzberger-Davis SM, Seufzer BJ, Shumway SD, Kurama T, Boothman DA, et al. NF-kappaB activation by camptothecin. alinkage between nuclear DNA damage and cytoplasmic signaling events. J Biol Chem. 2000;275:9501–9.

  16. 16.

    Huang TT, Wuerzberger-Davis SM, Wu ZH, Miyamoto S. Sequential modification of NEMO/IKKgamma by SUMO-1 and ubiquitin mediates NF-kappaB activation by genotoxic stress. Cell. 2003;115:565–76.

  17. 17.

    Wu ZH, Shi Y, Tibbetts RS, Miyamoto S. Molecular linkage between the kinase ATM and NF-kappaB signaling in response to genotoxic stimuli. Science. 2006;311:1141–6.

  18. 18.

    Ciccia A, Elledge SJ. The DNA damage response: making it safe to play with knives. Mol Cell. 2010;40:179–204.

  19. 19.

    Zeman MK, Cimprich KA. Causes and consequences of replication stress. Nat Cell Biol. 2014;16:2–9.

  20. 20.

    Bartkova J, Rezaei N, Liontos M, Karakaidos P, Kletsas D, Issaeva N, et al. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature. 2006;444:633–7.

  21. 21.

    Gorgoulis VG, Vassiliou LV, Karakaidos P, Zacharatos P, Kotsinas A, Liloglou T, et al. Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions. Nature. 2005;434:907–13.

  22. 22.

    Macheret M, Halazonetis TD. DNA replication stress as a hallmark of cancer. Annu Rev Pathol. 2015;10:425–48.

  23. 23.

    Zafar MK, Eoff RL. Translesion DNA synthesis in cancer: molecular mechanisms and therapeutic opportunities. Chem Res Toxicol. 2017;30:1942–55.

  24. 24.

    Allen C, Ashley AK, Hromas R, Nickoloff JA. More forks on the road to replication stress recovery. J Mol Cell Biol. 2011;3:4–12.

  25. 25.

    Mao Z, Bozzella M, Seluanov A, Gorbunova V. Comparison of nonhomologous end joining and homologous recombination in human cells. DNA Repair. 2008;7:1765–71.

  26. 26.

    O’Connor KW, Dejsuphong D, Park E, Nicolae CM, Kimmelman AC, D’Andrea AD, et al. PARI overexpression promotes genomic instability and pancreatic tumorigenesis. Cancer Res. 2013;73:2529–39.

  27. 27.

    Mochizuki AL, Katanaya A, Hayashi E, Hosokawa M, Moribe E, Motegi A. et al. PARI regulates stalled replication fork processing to maintain genome stability upon replication stress in mice. Mol Cell Biol. 2017;37:e00117-17

  28. 28.

    Moldovan GL, Dejsuphong D, Petalcorin MI, Hofmann K, Takeda S, Boulton SJ, et al. Inhibition of homologous recombination by the PCNA-interacting protein PARI. Mol Cell. 2012;45:75–86.

  29. 29.

    Burkovics P, Dome L, Juhasz S, Altmannova V, Sebesta M, Pacesa M, et al. The PCNA-associated protein PARI negatively regulates homologous recombination via the inhibition of DNA repair synthesis. Nucleic Acids Res. 2016;44:3176–89.

  30. 30.

    Bhat KP, Cortez D. RPA and RAD51: fork reversal, fork protection, and genome stability. Nat Struct Mol Biol. 2018;25:446–53.

  31. 31.

    Quinet A, Lemacon D, Vindigni A. Replication fork reversal: players and guardians. Mol Cell. 2017;68:830–3.

  32. 32.

    Piao L, Nakagawa H, Ueda K, Chung S, Kashiwaya K, Eguchi H. et al. C12orf48, termed PARP-1 binding protein, enhances poly(ADP-ribose) polymerase-1 (PARP-1) activity and protects pancreatic cancer cells from DNA damage. Genes Chromosomes Cancer. 2011;50:13–24.

  33. 33.

    Pitroda SP, Pashtan IM, Logan HL, Budke B, Darga TE, Weichselbaum RR, et al. DNA repair pathway gene expression score correlates with repair proficiency and tumor sensitivity to chemotherapy. Sci Transl Med. 2014;6:229ra242.

  34. 34.

    Pitroda SP, Bao R, Andrade J, Weichselbaum RR, Connell PP. Low recombination proficiency score (RPS) predicts heightened sensitivity to DNA-damaging chemotherapy in breast cancer. Clin Cancer Res. 2017;23:4493–500.

  35. 35.

    Xie C, Drenberg C, Edwards H, Caldwell JT, Chen W, Inaba H, et al. Panobinostat enhances cytarabine and daunorubicin sensitivities in AML cells through suppressing the expression of BRCA1, CHK1, and Rad51. PLoS ONE. 2013;8:e79106.

  36. 36.

    Song C, Gowda C, Pan X, Ding Y, Tong Y, Tan BH, et al. Targeting casein kinase II restores Ikaros tumor suppressor activity and demonstrates therapeutic efficacy in high-risk leukemia. Blood. 2015;126:1813–22.

  37. 37.

    Vassen L, Duhrsen U, Kosan C, Zeng H, Moroy T. Growth factor independence 1 (Gfi1) regulates cell-fate decision of a bipotential granulocytic-monocytic precursor defined by expression of Gfi1 and CD48. Am J Blood Res. 2012;2:228–42.

  38. 38.

    Ammon C, Meyer SP, Schwarzfischer L, Krause SW, Andreesen R, Kreutz M. Comparative analysis of integrin expression on monocyte-derived macrophages and monocyte-derived dendritic cells. Immunology. 2000;100:364–9.

  39. 39.

    Wang X, Pesakhov S, Harrison JS, Danilenko M, Studzinski GP. ERK5 pathway regulates transcription factors important for monocytic differentiation of human myeloid leukemia cells. J Cell Physiol. 2014;229:856–67.

  40. 40.

    Zhao KW, Li X, Zhao Q, Huang Y, Li D, Peng ZG, et al. Protein kinase Cdelta mediates retinoic acid and phorbol myristate acetate-induced phospholipid scramblase 1 gene expression: its role in leukemic cell differentiation. Blood. 2004;104:3731–8.

  41. 41.

    Wang J, Xiang G, Mitchelson K, Zhou Y. Microarray profiling of monocytic differentiation reveals miRNA–mRNA intrinsic correlation. J Cell Biochem. 2011;112:2443–53.

  42. 42.

    Vallerga MB, Mansilla SF, Federico MB, Bertolin AP, Gottifredi V. Rad51 recombinase prevents Mre11 nuclease-dependent degradation and excessive PrimPol-mediated elongation of nascent DNA after UV irradiation. Proc Natl Acad Sci USA. 2015;112:E6624–6633.

  43. 43.

    Zellweger R, Dalcher D, Mutreja K, Berti M, Schmid JA, Herrador R, et al. Rad51-mediated replication fork reversal is a global response to genotoxic treatments in human cells. J Cell Biol. 2015;208:563–79.

  44. 44.

    Lim DS, Hasty P. A mutation in mouse rad51 results in an early embryonic lethal that is suppressed by a mutation in p53. Mol Cell Biol. 1996;16:7133–43.

  45. 45.

    Tsuzuki T, Fujii Y, Sakumi K, Tominaga Y, Nakao K, Sekiguchi M, et al. Targeted disruption of the Rad51 gene leads to lethality in embryonic mice. Proc Natl Acad Sci USA. 1996;93:6236–40.

  46. 46.

    Yoon SW, Kim DK, Kim KP, Park KS. Rad51 regulates cell cycle progression by preserving G2/M transition in mouse embryonic stem cells. Stem Cells Dev. 2014;23:2700–11.

  47. 47.

    Hayden MS, Ghosh S. NF-kappaB the first quarter-century: remarkable progress and outstanding questions. Genes Dev. 2012;26:203–34.

  48. 48.

    Tilstra JS, Clauson CL, Niedernhofer LJ, Robbins PD. NF-kappaB in aging and disease. Aging Dis. 2011;2:449–65.

  49. 49.

    Cancer Genome Atlas Research N, Ley TJ, Miller C, Ding L, Raphael BJ, Mungall AJ, et al. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013;368:2059–74.

  50. 50.

    Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013;6:pl1.

  51. 51.

    Choe KN, Nicolae CM, Constantin D, Imamura Kawasawa Y, Delgado-Diaz MR, De S, et al. HUWE1 interacts with PCNA to alleviate replication stress. EMBO Rep. 2016;17:874–86.

  52. 52.

    Schleicher EM, Galvan AM, Imamura-Kawasawa Y, Moldovan GL, Nicolae CM. PARP10 promotes cellular proliferation and tumorigenesis by alleviating replication stress. Nucleic Acids Res. 2018;46:8898–907.

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Acknowledgments

We would like to thank Dr. Alan D’Andrea for EUFA130 cells, Dr. Chandrika Gowda for experimental advice, Daniel Constantin for technical support, and the Penn State College of Medicine Flow Cytometry and Genome Sciences cores. This work was supported by: the Department of Defense (award CA140303) and the St. Baldrick Foundation (to GLM); NIH R01CA209829, R01CA213912, Alex’s Lemonade Stand, Hyundai Hope on Wheels Scholar Grant, and Bear Necessities Pediatric Cancer Foundation (to SD).

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Correspondence to George-Lucian Moldovan.

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