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PTIP functions broadly to catalyze histone methylation in DNA damage repair and within the hematopoietic lineage, to promote immunoglobulin variable region (variable, diversity, joining [VDJ]) and class switch recombination (CSR). In this report, we show that a fraction of PTIP is actively transported from the nucleus to mitochondria resulting in their aggregation, release of cytochrome c into the cytoplasm and cellular apoptosis. Deletion of an N-terminal glutamine-rich region (QR), mutation of a conserved threonine within BRCT3 and truncation of the C-terminal BRCT5 domain each significantly reduced apoptosis as well as its previously documented G2\/M cell cycle function. This is the first report to identify a mitochondrial-based apoptotic mechanism employed by the PTIP transcription factor.<\/jats:p>","DOI":"10.33696\/signaling.6.142","type":"journal-article","created":{"date-parts":[[2026,1,25]],"date-time":"2026-01-25T14:25:18Z","timestamp":1769351118000},"page":"126","source":"Crossref","is-referenced-by-count":2,"title":["PAX-Interacting Protein 1 (PTIP) Promotes Apoptosis"],"prefix":"10.33696","volume":"6","author":[{"given":"Ching-Jung","family":"Huang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Cho","family":"Hyein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kangsan","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danyang","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daechan","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y. Jessie","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haley O.","family":"Tucker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"18993","published-online":{"date-parts":[[2025,11,29]]},"reference":[{"key":"ref0","doi-asserted-by":"crossref","unstructured":"1.\tLechner MS, Levitan I, Dressler GR. PTIP, a novel BRCT domain-containing protein interacts with Pax2 and is associated with active chromatin. Nucleic Acids Res. 2000 Jul 15;28(14):2741\u201351.","DOI":"10.1093\/nar\/28.14.2741"},{"key":"ref1","doi-asserted-by":"crossref","unstructured":"2.\tPe\u00f1a-Guerrero J, Fern\u00e1ndez-Rubio C, Garc\u00eda-Sosa AT, Nguewa PA. BRCT Domains: Structure, Functions, and Implications in Disease-New Therapeutic Targets for Innovative Drug Discovery against Infections. Pharmaceutics. 2023 Jun 27;15(7):1839.","DOI":"10.3390\/pharmaceutics15071839"},{"key":"ref2","doi-asserted-by":"crossref","unstructured":"3.\tIsmail T, Alzneika S, Riguene E, Al-Maraghi S, Alabdulrazzak A, Al-Khal N, et al. BRCA1 and Its Vulnerable C-Terminal BRCT Domain: Structure, Function, Genetic Mutations and Links to Diagnosis and Treatment of Breast and Ovarian Cancer. Pharmaceuticals (Basel). 2024 Mar 4;17(3):333.","DOI":"10.3390\/ph17030333"},{"key":"ref3","doi-asserted-by":"crossref","unstructured":"4.\tCallen E, Faryabi RB, Luckey M, Hao B, Daniel JA, Yang W, et al. The DNA damage- and transcription-associated protein paxip1 controls thymocyte development and emigration. Immunity. 2012 Dec 14;37(6):971\u201385.","DOI":"10.1016\/j.immuni.2012.10.007"},{"key":"ref4","doi-asserted-by":"crossref","unstructured":"5.\tCyster JG, Wilson PC. Antibody modulation of B cell responses-Incorporating positive and negative feedback. Immunity. 2024 Jul 9;57(7):1466\u201381.","DOI":"10.1016\/j.immuni.2024.06.009"},{"key":"ref5","doi-asserted-by":"crossref","unstructured":"6.\tCobaleda C, Schebesta A, Delogu A, Busslinger M. Pax5: the guardian of B cell identity and function. Nat Immunol. 2007 May;8(5):463\u201370.","DOI":"10.1038\/ni1454"},{"key":"ref6","doi-asserted-by":"crossref","unstructured":"7.\tSchwab KR, Patel SR, Dressler GR. Role of PTIP in class switch recombination and long-range chromatin interactions at the immunoglobulin heavy chain locus. Mol Cell Biol. 2011 Apr;31(7):1503\u201311.","DOI":"10.1128\/MCB.00990-10"},{"key":"ref7","doi-asserted-by":"crossref","unstructured":"8.\tPatel SR, Kim D, Levitan I, Dressler GR. The BRCT-domain containing protein PTIP links PAX2 to a histone H3, lysine 4 methyltransferase complex. Dev Cell. 2007 Oct;13(4):580\u201392.","DOI":"10.1016\/j.devcel.2007.09.004"},{"key":"ref8","doi-asserted-by":"crossref","unstructured":"9.\tStarnes LM, Su D, Pikkupeura LM, Weinert BT, Santos MA, Mund A, et al. A PTIP-PA1 subcomplex promotes transcription for IgH class switching independently from the associated MLL3\/MLL4 methyltransferase complex. Genes Dev. 2016 Jan 15;30(2):149\u201363.","DOI":"10.1101\/gad.268797.115"},{"key":"ref9","doi-asserted-by":"crossref","unstructured":"10.\tDaniel JA, Santos MA, Wang Z, Zang C, Schwab KR, Jankovic M, et al. PTIP promotes chromatin changes critical for immunoglobulin class switch recombination. Science. 2010 Aug 20;329(5994):917\u201323.","DOI":"10.1126\/science.1187942"},{"key":"ref10","doi-asserted-by":"crossref","unstructured":"11.\tDaniel JA, Nussenzweig A. The AID-induced DNA damage response in chromatin. Mol Cell. 2013 May 9;50(3):309\u201321.","DOI":"10.1016\/j.molcel.2013.04.017"},{"key":"ref11","doi-asserted-by":"crossref","unstructured":"12.\tNewton K, Strasser A, Kayagaki N, Dixit VM. Cell death. Cell. 2024 Jan 18;187(2):235\u201356.","DOI":"10.1016\/j.cell.2023.11.044"},{"key":"ref12","doi-asserted-by":"crossref","unstructured":"13.\tMu\u00f1oz IM, Rouse J. Control of histone methylation and genome stability by PTIP. EMBO Rep. 2009 Mar;10(3):239\u201345.","DOI":"10.1038\/embor.2009.21"},{"key":"ref13","doi-asserted-by":"crossref","unstructured":"14.\tSaka Y, Esashi F, Matsusaka T, Mochida S, Yanagida M. Damage and replication checkpoint control in fission yeast is ensured by interactions of Crb2, a protein with BRCT motif, with Cut5 and Chk1. Genes Dev. 1997 Dec 15;11(24):3387\u2013400.","DOI":"10.1101\/gad.11.24.3387"},{"key":"ref14","doi-asserted-by":"crossref","unstructured":"15.\tChinnaiyan AM, O'Rourke K, Tewari M, Dixit VM. FADD, a novel death domain-containing protein, interacts with the death domain of Fas and initiates apoptosis. Cell. 1995 May 19;81(4):505\u201312.","DOI":"10.1016\/0092-8674(95)90071-3"},{"key":"ref15","doi-asserted-by":"crossref","unstructured":"16.\tHsu H, Shu HB, Pan MG, Goeddel DV. TRADD-TRAF2 and TRADD-FADD interactions define two distinct TNF receptor 1 signal transduction pathways. Cell. 1996 Jan 26;84(2):299\u2013308.","DOI":"10.1016\/S0092-8674(00)80984-8"},{"key":"ref16","doi-asserted-by":"crossref","unstructured":"17.\tHueber AO, Z\u00f6rnig M, Lyon D, Suda T, Nagata S, Evan GI. Requirement for the CD95 receptor-ligand pathway in c-Myc-induced apoptosis. Science. 1997 Nov 14;278(5341):1305\u20139.","DOI":"10.1126\/science.278.5341.1305"},{"key":"ref17","doi-asserted-by":"crossref","unstructured":"18.\tGottlieb E, Haffner R, von R\u00fcden T, Wagner EF, Oren M. Down-regulation of wild-type p53 activity interferes with apoptosis of IL-3-dependent hematopoietic cells following IL-3 withdrawal. EMBO J. 1994 Mar 15;13(6):1368\u201374.","DOI":"10.1002\/j.1460-2075.1994.tb06390.x"},{"key":"ref18","doi-asserted-by":"crossref","unstructured":"19.\tShaulian E, Zauberman A, Ginsberg D, Oren M. Identification of a minimal transforming domain of p53: negative dominance through abrogation of sequence-specific DNA binding. Mol Cell Biol. 1992 Dec;12(12):5581\u201392.","DOI":"10.1128\/MCB.12.12.5581"},{"key":"ref19","unstructured":"20.\tAddison C, Jenkins JR, St\u00fcrzbecher HW. The p53 nuclear localisation signal is structurally linked to a p34cdc2 kinase motif. Oncogene. 1990 Mar;5(3):423\u20136."},{"key":"ref20","doi-asserted-by":"crossref","unstructured":"21.\tRobbins J, Dilworth SM, Laskey RA, Dingwall C. Two interdependent basic domains in nucleoplasmin nuclear targeting sequence: identification of a class of bipartite nuclear targeting sequence. Cell. 1991 Feb 8;64(3):615\u201323.","DOI":"10.1016\/0092-8674(91)90245-T"},{"key":"ref21","doi-asserted-by":"crossref","unstructured":"22.\tLu J, Wu T, Zhang B, Liu S, Song W, Qiao J, et al. Types of nuclear localization signals and mechanisms of protein import into the nucleus. Cell Commun Signal. 2021 May 22;19(1):60.","DOI":"10.1186\/s12964-021-00741-y"},{"key":"ref22","doi-asserted-by":"crossref","unstructured":"23.\tJung Y, Kraikivski P, Shafiekhani S, Terhune SS, Dash RK. Crosstalk between Plk1, p53, cell cycle, and G2\/M DNA damage checkpoint regulation in cancer: computational modeling and analysis. NPJ Syst Biol Appl. 2021 Dec 9;7(1):46.","DOI":"10.1038\/s41540-021-00203-8"},{"key":"ref23","doi-asserted-by":"crossref","unstructured":"24.\tWardlaw CP, Carr AM, Oliver AW. TopBP1: A BRCT-scaffold protein functioning in multiple cellular pathways. DNA Repair (Amst). 2014 Oct;22:165\u201374.","DOI":"10.1016\/j.dnarep.2014.06.004"},{"key":"ref24","doi-asserted-by":"crossref","unstructured":"25.\tGao Y, Jiao Y, Gong X, Liu J, Xiao H, Zheng Q. Role of transcription factors in apoptotic cells clearance. Front Cell Dev Biol. 2023 Jan 19;11:1110225.","DOI":"10.3389\/fcell.2023.1110225"},{"key":"ref25","doi-asserted-by":"crossref","unstructured":"26.\tLiu Y, Su Z, Tavana O, Gu W. Understanding the complexity of p53 in a new era of tumor suppression. Cancer Cell. 2024 Jun 10;42(6):946\u201367.","DOI":"10.1016\/j.ccell.2024.04.009"},{"key":"ref26","doi-asserted-by":"crossref","unstructured":"27.\tLin B, Kolluri SK, Lin F, Liu W, Han YH, Cao X, et al. Conversion of Bcl-2 from protector to killer by interaction with nuclear orphan receptor Nur77\/TR3. Cell. 2004 Feb 20;116(4):527\u201340.","DOI":"10.1016\/S0092-8674(04)00162-X"},{"key":"ref27","doi-asserted-by":"crossref","unstructured":"28.\tMassacci G, Perfetto L, Sacco F. The Cyclin-dependent kinase 1: more than a cell cycle regulator. Br J Cancer. 2023 Nov;129(11):1707\u201316.","DOI":"10.1038\/s41416-023-02468-8"},{"key":"ref28","doi-asserted-by":"crossref","unstructured":"29.\tRoy PK, Biswas A, K D, Mandal M. An insight into the ubiquitin-proteasomal axis and related therapeutic approaches towards central nervous system malignancies. Biochim Biophys Acta Rev Cancer. 2022 May;1877(3):188734.","DOI":"10.1016\/j.bbcan.2022.188734"},{"key":"ref29","doi-asserted-by":"crossref","unstructured":"30.\tLieberman AP, Shakkottai VG, Albin RL. Polyglutamine Repeats in Neurodegenerative Diseases. Annu Rev Pathol. 2019 Jan 24;14:1\u201327.","DOI":"10.1146\/annurev-pathmechdis-012418-012857"},{"key":"ref30","doi-asserted-by":"crossref","unstructured":"31.\tBrouillet E, Hantraye P, Ferrante RJ, Dolan R, Leroy-Willig A, Kowall NW, et al. Chronic mitochondrial energy impairment produces selective striatal degeneration and abnormal choreiform movements in primates. Proc Natl Acad Sci U S A. 1995 Jul 18;92(15):7105\u20139.","DOI":"10.1073\/pnas.92.15.7105"},{"key":"ref31","doi-asserted-by":"crossref","unstructured":"32.\tFerro A, Carbone E, Zhang J, Marzouk E, Villegas M, Siegel A, et al. Short-term succinic acid treatment mitigates cerebellar mitochondrial OXPHOS dysfunction, neurodegeneration and ataxia in a Purkinje-specific spinocerebellar ataxia type 1 (SCA1) mouse model. PLoS One. 2017 Dec 6;12(12):e0188425.","DOI":"10.1371\/journal.pone.0188425"},{"key":"ref32","doi-asserted-by":"crossref","unstructured":"33.\tWang X, Takenaka K, Takeda S. PTIP promotes DNA double-strand break repair through homologous recombination. Genes Cells. 2010 Mar;15(3):243\u201354.","DOI":"10.1111\/j.1365-2443.2009.01379.x"},{"key":"ref33","doi-asserted-by":"crossref","unstructured":"34.\tNakata Y, Nagasawa S, Sera Y, Yamasaki N, Kanai A, Kobatake K, et al. PTIP epigenetically regulates DNA damage-induced cell cycle arrest by upregulating PRDM1. Sci Rep. 2024 Aug 3;14(1):17987.","DOI":"10.1038\/s41598-024-68295-w"},{"key":"ref34","doi-asserted-by":"crossref","unstructured":"35.\tReinhardt HC, Yaffe MB. Phospho-Ser\/Thr-binding domains: navigating the cell cycle and DNA damage response. Nat Rev Mol Cell Biol. 2013 Sep;14(9):563\u201380.","DOI":"10.1038\/nrm3640"},{"key":"ref35","doi-asserted-by":"crossref","unstructured":"36.\tJayaraj GG, Hipp MS, Hartl FU. Functional Modules of the Proteostasis Network. Cold Spring Harb Perspect Biol. 2020 Jan 2;12(1):a033951.","DOI":"10.1101\/cshperspect.a033951"},{"key":"ref36","doi-asserted-by":"crossref","unstructured":"37.\tFoo TK, Vincelli G, Huselid E, Her J, Zheng H, Simhadri S, et al. ATR\/ATM-Mediated Phosphorylation of BRCA1 T1394 Promotes Homologous Recombinational Repair and G2-M Checkpoint Maintenance. Cancer Res. 2021 Sep 15;81(18):4676\u201384.","DOI":"10.1158\/0008-5472.CAN-20-2723"},{"key":"ref37","doi-asserted-by":"crossref","unstructured":"38.\tSora V, Papaleo E. Structural Details of BH3 Motifs and BH3-Mediated Interactions: an Updated Perspective. Front Mol Biosci. 2022 May 24;9:864874.","DOI":"10.3389\/fmolb.2022.864874"},{"key":"ref38","doi-asserted-by":"crossref","unstructured":"39.\tBykov YS, Flohr T, Boos F, Zung N, Herrmann JM, Schuldiner M. Widespread use of unconventional targeting signals in mitochondrial ribosome proteins. EMBO J. 2022 Jan 4;41(1):e109519.","DOI":"10.15252\/embj.2021109519"},{"key":"ref39","doi-asserted-by":"crossref","unstructured":"40.\tKoszela J, Rintala-Dempsey A, Salzano G, Pimenta V, Kamarainen O, Gabrielsen M, et al. A substrate-interacting region of Parkin directs ubiquitination of the mitochondrial GTPase Miro1. bioRxiv [Preprint]. 2024 Jun 3:2024.06.03.597144.","DOI":"10.1101\/2024.06.03.597144"},{"key":"ref40","doi-asserted-by":"crossref","unstructured":"41.\tTorun A, Tu\u011fral H, Banerjee S. Crosstalk Between Phase-Separated Membraneless Condensates and Membrane-Bound Organelles in Cellular Function and Disease. Adv Exp Med Biol. 2025;1483:141\u201369.","DOI":"10.1007\/5584_2025_852"},{"key":"ref41","doi-asserted-by":"crossref","unstructured":"42.\tCao M, Zhang X, Wang X, Zhao D, Shi M, Zou J, et al. An Overview of Liquid-Liquid Phase Separation and Its Mechanisms in Sepsis. J Inflamm Res. 2025 Mar 17;18:3969\u201380.","DOI":"10.2147\/JIR.S513098"},{"key":"ref42","doi-asserted-by":"crossref","unstructured":"43.\tFujikawa D, Nakamura T, Yoshioka D, Li Z, Moriizumi H, Taguchi M, et al. Stress granule formation inhibits stress-induced apoptosis by selectively sequestering executioner caspases. Curr Biol. 2023 May 22;33(10):1967\u201381.e8.","DOI":"10.1016\/j.cub.2023.04.012"},{"key":"ref43","doi-asserted-by":"crossref","unstructured":"44.\tYan W, Shao Z, Li F, Niu L, Shi Y, Teng M, et al. Structural basis of \u03b3H2AX recognition by human PTIP BRCT5-BRCT6 domains in the DNA damage response pathway. FEBS Lett. 2011 Dec 15;585(24):3874\u20139.","DOI":"10.1016\/j.febslet.2011.10.045"},{"key":"ref44","doi-asserted-by":"crossref","unstructured":"45.\tJug\u00e9 R, Breugnot J, Da Silva C, Bordes S, Closs B, Aouacheria A. Quantification and Characterization of UVB-Induced Mitochondrial Fragmentation in Normal Primary Human Keratinocytes. 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