Marta Seczynska

All Publications

• The sound of silence: mechanisms and implications of HUSH complex function Trends in Genetics Seczynska, M., Lehner, P. J. 2023

  View details for DOI 10.1016/j.tig.2022.12.005

• Genome surveillance by HUSH-mediated silencing of intronless mobile elements NATURE Seczynska, M., Bloor, S., Cuesta, S., Lehner, P. J. 2022; 601 (7893): 440-+

  Abstract

  All life forms defend their genome against DNA invasion. Eukaryotic cells recognize incoming DNA and limit its transcription through repressive chromatin modifications. The human silencing hub (HUSH) complex transcriptionally represses long interspersed element-1 retrotransposons (L1s) and retroviruses through histone H3 lysine 9 trimethylation (H3K9me3)1-3. How HUSH recognizes and initiates silencing of these invading genetic elements is unknown. Here we show that HUSH is able to recognize and transcriptionally repress a broad range of long, intronless transgenes. Intron insertion into HUSH-repressed transgenes counteracts repression, even in the absence of intron splicing. HUSH binds transcripts from the target locus, prior to and independent of H3K9me3 deposition, and target transcription is essential for both initiation and propagation of HUSH-mediated H3K9me3. Genomic data reveal how HUSH binds and represses a subset of endogenous intronless genes generated through retrotransposition of cellular mRNAs. Thus intronless cDNA-the hallmark of reverse transcription-provides a versatile way to distinguish invading retroelements from host genes and enables HUSH to protect the genome from 'non-self' DNA, despite there being no previous exposure to the invading element. Our findings reveal the existence of a transcription-dependent genome-surveillance system and explain how it provides immediate protection against newly acquired elements while avoiding inappropriate repression of host genes.

  View details for DOI 10.1038/s41586-021-04228-1

  View details for Web of Science ID 000741978600002

  View details for PubMedID 34794168

  View details for PubMedCentralID PMC8770142

• TASOR is a pseudo-PARP that directs HUSH complex assembly and epigenetic transposon control NATURE COMMUNICATIONS Douse, C. H., Tchasovnikarova, I. A., Timms, R. T., Protasio, A. V., Seczynska, M., Prigozhin, D. M., Albecka, A., Wagstaff, J., Williamson, J. C., Freund, S. V., Lehner, P. J., Modis, Y. 2020; 11 (1): 4940

  Abstract

  The HUSH complex represses retroviruses, transposons and genes to maintain the integrity of vertebrate genomes. HUSH regulates deposition of the epigenetic mark H3K9me3, but how its three core subunits - TASOR, MPP8 and Periphilin - contribute to assembly and targeting of the complex remains unknown. Here, we define the biochemical basis of HUSH assembly and find that its modular architecture resembles the yeast RNA-induced transcriptional silencing complex. TASOR, the central HUSH subunit, associates with RNA processing components. TASOR is required for H3K9me3 deposition over LINE-1 repeats and repetitive exons in transcribed genes. In the context of previous studies, this suggests that an RNA intermediate is important for HUSH activity. We dissect the TASOR and MPP8 domains necessary for transgene repression. Structure-function analyses reveal TASOR bears a catalytically-inactive PARP domain necessary for targeted H3K9me3 deposition. We conclude that TASOR is a multifunctional pseudo-PARP that directs HUSH assembly and epigenetic regulation of repetitive genomic targets.

  View details for DOI 10.1038/s41467-020-18761-6

  View details for Web of Science ID 000577121500003

  View details for PubMedID 33009411

  View details for PubMedCentralID PMC7532188

• A selective ER-phagy exerts procollagen quality control via a Calnexin-FAM134B complex EMBO JOURNAL Forrester, A., De Leonibus, C., Grumati, P., Fasana, E., Piemontese, M., Staiano, L., Fregno, I., Raimondi, A., Marazza, A., Bruno, G., Iavazzo, M., Intartaglia, D., Seczynska, M., van Anken, E., Conte, I., De Matteis, M., Dikic, I., Molinari, M., Settembre, C. 2019; 38 (2)

  Abstract

  Autophagy is a cytosolic quality control process that recognizes substrates through receptor-mediated mechanisms. Procollagens, the most abundant gene products in Metazoa, are synthesized in the endoplasmic reticulum (ER), and a fraction that fails to attain the native structure is cleared by autophagy. However, how autophagy selectively recognizes misfolded procollagens in the ER lumen is still unknown. We performed siRNA interference, CRISPR-Cas9 or knockout-mediated gene deletion of candidate autophagy and ER proteins in collagen producing cells. We found that the ER-resident lectin chaperone Calnexin (CANX) and the ER-phagy receptor FAM134B are required for autophagy-mediated quality control of endogenous procollagens. Mechanistically, CANX acts as co-receptor that recognizes ER luminal misfolded procollagens and interacts with the ER-phagy receptor FAM134B. In turn, FAM134B binds the autophagosome membrane-associated protein LC3 and delivers a portion of ER containing both CANX and procollagen to the lysosome for degradation. Thus, a crosstalk between the ER quality control machinery and the autophagy pathway selectively disposes of proteasome-resistant misfolded clients from the ER.

  View details for DOI 10.15252/embj.201899847

  View details for Web of Science ID 000455915300015

  View details for PubMedID 30559329

  View details for PubMedCentralID PMC6331724

• Lack of Heme Oxygenase-1 Induces Inflammatory Reaction and Proliferation of Muscle Satellite Cells after Cardiotoxin-Induced Skeletal Muscle Injury AMERICAN JOURNAL OF PATHOLOGY Kozakowska, M., Pietraszek-Gremplewicz, K., Ciesla, M., Seczynska, M., Bronisz-Budzynska, I., Podkalicka, P., Bukowska-Strakova, K., Loboda, A., Jozkowicz, A., Dulak, J. 2018; 188 (2): 491-506

  Abstract

  Heme oxygenase-1 (HO-1, Hmox1) regulates viability, proliferation, and differentiation of many cell types; hence, it may affect regeneration of injured skeletal muscle. Here, we injected cardiotoxin into gastrocnemius muscle of Hmox1+/+ and Hmox1-/- animals and analyzed cellular response after muscle injury, focusing on muscle satellite cells (SCs), inflammatory reaction, fibrosis, and formation of new blood vessels. HO-1 is strongly induced after muscle injury, being expressed mostly in the infiltrating leukocytes (CD45+ cells), including macrophages (F4/80+ cells). Lack of HO-1 augments skeletal muscle injury, evidenced by increased creatinine kinase and lactate dehydrogenase, as well as expression of monocyte chemoattractant protein-1, IL-6, IL-1β, and insulin-like growth factor-1. This, together with disturbed proportion of M1/M2 macrophages, accompanied by enhanced formation of arterioles, may be responsible for shift of Hmox1-/- myofiber size distribution toward larger one. Importantly, HO-1-deficient SCs are prone to activation and have higher proliferation on injury. This effect can be partially mimicked by stimulation of Hmox1+/+ SCs with monocyte chemoattractant protein-1, IL-6, IL-1β, and is associated with increased MyoD expression, suggesting that Hmox1-/- SCs are shifted toward more differentiated myogenic population. However, multiple rounds of degeneration/regeneration in conditions of HO-1 deficiency may lead to exhaustion of SC pool, and the number of SCs is decreased in old Hmox1-/- mice. In summary, HO-1 modulates muscle repair mechanisms preventing its uncontrolled acceleration.

  View details for DOI 10.1016/j.ajpath.2017.10.017

  View details for Web of Science ID 000423256300020

  View details for PubMedID 29169990

• Removing the waste bags: how p97 drives autophagy of lysosomes EMBO JOURNAL Seczynska, M., Dikic, I. 2017; 36 (2): 129-131

  View details for DOI 10.15252/embj.201695950

  View details for Web of Science ID 000393317800001

  View details for PubMedID 27895087

  View details for PubMedCentralID PMC5242383

• Heme oxygenase-1 controls an HDAC4-miR-206 pathway of oxidative stress in rhabdomyosarcoma. Cancer research Ciesla, M., Marona, P., Kozakowska, M., Jez, M., Seczynska, M., Loboda, A., Bukowska-Strakova, K., Szade, A., Walawender, M., Kusior, M., Stepniewski, J., Szade, K., Krist, B., Yagensky, O., Urbanik, A., Kazanowska, B., Dulak, J., Jozkowicz, A. 2016

  Abstract

  Rhabdomyosarcoma (RMS) is an aggresive soft tissue cancer characterized by disturbed myogenic differentiation. Here we report a role for the oxidative stress response factor HO-1 in progression of RMS. We found that HO-1 was elevated and its effector target miR-206 decreased in RMS cell lines and clinical primary tumors of the more aggressive alveolar phenotype (aRMS). In embryonal RMS (eRMS), HO-1 expression was induced by Pax3/7-FoxO1, an aRMS hallmark oncogene, followed by drop in miR-206 levels. Inhibition of HO-1 by tin protoporphyrin (SnPP) or siRNA downregulated Pax3/7-FoxO1 target genes and induced a myogenic program in RMS. These effects were not mediated by altered myoD expression, instead, cells with elevated HO-1 produced less ROS resulting in nuclear localization of HDAC4 and miR-206 repression. HO-1 inhibition by SnPP reduced growth and vascularization of RMS tumors in vivo accompanied by induction of miR-206. Effects of SnPP on miR-206 expression and RMS tumor growth were mimicked by pharmacological inhibition of HDAC. Thus, HO-1 inhibition activates an miR-206-dependent myogenic program in RMS, offering a novel therapeutic strategy for treatment of this malignancy.

  View details for DOI 10.1158/0008-5472.CAN-15-1883

  View details for PubMedID 27488535

• IL28B polymorphism (rs12979860) associated with clearance of HCV infection in Poland: Systematic review of its prevalence in chronic hepatitis C patients and general population frequency PHARMACOLOGICAL REPORTS Kaczor, M. P., Seczynska, M., Szczeklik, W., Sanak, M. 2015; 67 (2): 260-266

  Abstract

  A common single nucleotide polymorphism (rs12979860) of the interleukin-28B (IL28B) gene is strongly associated with spontaneous and treatment-related eradication of HCV infection. In this study we estimated rs12979860 genotypes distribution among chronic hepatitis C patients in Poland using a systematic review of published studies and compared this data with the prevalence of rs12979860 variants of IL28B in representative sample of the Southern Poland population.Systematic review on rs12979860 variant prevalence in the Polish chronic HCV subjects was performed. Additionally, age- and gender-stratified population sample was recruited from inhabitants of Kraków using a randomized municipal census data, DNA samples available for 538 individuals were genotyped using a real-time PCR method.The frequency of homozygotes TT was from 15 to 27% and carriers of unfavorable T alleles (genotypes CT and TT) were present in 70-80% of chronic HCV subjects. In the general population, 47% individuals were CC homozygous, 42% CT heterozygous and 11% TT homozygous. The population frequency of T allele was 0.318 (95% CI: 0.291-0.347) and the variant was in Hardy-Weinberg equilibrium. Distributions of IL28B genotypes in chronic HCV patients were characterized by a departure from the genetic equilibrium and differed significantly from the random population sample.Events of spontaneous viral clearance can fully explain differences between genotype distributions in general population and chronic HCV subjects and a departure from the genetic equilibrium. This is the first study estimating the prevalence of IL28B rs12979860 SNP in the Southern Poland population based on a random representative sample.

  View details for DOI 10.1016/j.pharep.2014.10.006

  View details for Web of Science ID 000350611900013

  View details for PubMedID 25712648