Aya Awad

All Publications

• The many faces of the helicase RTEL1 at telomeres and beyond. Trends in cell biology Hourvitz, N., Awad, A., Tzfati, Y. 2024; 34 (2): 109-121

  Abstract

  Regulator of telomere elongation 1 (RTEL1) is known as a DNA helicase that is important for telomeres and genome integrity. However, the diverse phenotypes of RTEL1 dysfunction, the wide spectrum of symptoms caused by germline RTEL1 mutations, and the association of RTEL1 mutations with cancers suggest that RTEL1 is a complex machine that interacts with DNA, RNA, and proteins, and functions in diverse cellular pathways. We summarize the proposed functions of RTEL1 and discuss their implications for telomere maintenance. Studying RTEL1 is crucial for understanding the complex interplay between telomere maintenance and other nuclear pathways, and how compromising these pathways causes telomere biology diseases, various aging-associated pathologies, and cancer.

  View details for DOI 10.1016/j.tcb.2023.07.002

  View details for PubMedID 37532653

• Science bridges political barriers. Cell Awad, A. 2023; 186 (6): 1088-1091

  Abstract

  Aya Awad is a graduate of the Science Training Encouraging Peace (STEP) program. The STEP program funds pairs of Israeli and Palestinian students to study together for the length of their graduate degrees. She writes about the friendship she developed with her STEP partner and how science bridged political barriers.

  View details for DOI 10.1016/j.cell.2023.02.013

  View details for PubMedID 36931237

• Inherited human Apollo deficiency causes severe bone marrow failure and developmental defects. Blood Kermasson, L., Churikov, D., Awad, A., Smoom, R., Lainey, E., Touzot, F., Audebert-Bellanger, S., Haro, S., Roger, L., Costa, E., Mouf, M., Bottero, A., Oleastro, M., Abdo, C., de Villartay, J. P., Géli, V., Tzfati, Y., Callebaut, I., Danielian, S., Soares, G., Kannengiesser, C., Revy, P. 2022; 139 (16): 2427-2440

  Abstract

  Inherited bone marrow failure syndromes (IBMFSs) are a group of disorders typified by impaired production of 1 or several blood cell types. The telomere biology disorders dyskeratosis congenita (DC) and its severe variant, Høyeraal-Hreidarsson (HH) syndrome, are rare IBMFSs characterized by bone marrow failure, developmental defects, and various premature aging complications associated with critically short telomeres. We identified biallelic variants in the gene encoding the 5'-to-3' DNA exonuclease Apollo/SNM1B in 3 unrelated patients presenting with a DC/HH phenotype consisting of early-onset hypocellular bone marrow failure, B and NK lymphopenia, developmental anomalies, microcephaly, and/or intrauterine growth retardation. All 3 patients carry a homozygous or compound heterozygous (in combination with a null allele) missense variant affecting the same residue L142 (L142F or L142S) located in the catalytic domain of Apollo. Apollo-deficient cells from patients exhibited spontaneous chromosome instability and impaired DNA repair that was complemented by CRISPR/Cas9-mediated gene correction. Furthermore, patients' cells showed signs of telomere fragility that were not associated with global reduction of telomere length. Unlike patients' cells, human Apollo KO HT1080 cell lines showed strong telomere dysfunction accompanied by excessive telomere shortening, suggesting that the L142S and L142F Apollo variants are hypomorphic. Collectively, these findings define human Apollo as a genome caretaker and identify biallelic Apollo variants as a genetic cause of a hitherto unrecognized severe IBMFS that combines clinical hallmarks of DC/HH with normal telomere length.

  View details for DOI 10.1182/blood.2021010791

  View details for PubMedID 35007328

  View details for PubMedCentralID PMC11022855

• An RTEL1 Mutation Links to Infantile-Onset Ulcerative Colitis and Severe Immunodeficiency. Journal of clinical immunology Ziv, A., Werner, L., Konnikova, L., Awad, A., Jeske, T., Hastreiter, M., Mitsialis, V., Stauber, T., Wall, S., Kotlarz, D., Klein, C., Snapper, S. B., Tzfati, Y., Weiss, B., Somech, R., Shouval, D. S. 2020; 40 (7): 1010-1019

  Abstract

  More than 50 different monogenic disorders causing inflammatory bowel disease (IBD) have been identified. Our goal was to characterize the clinical phenotype, genetic workup, and immunologic alterations in an Ashkenazi Jewish patient that presented during infancy with ulcerative colitis and unique clinical manifestations.Immune workup and whole-exome sequencing were performed, along with Sanger sequencing for confirmation. Next-generation sequencing of the TCRB and IgH was conducted for immune repertoire analysis. Telomere length was evaluated by in-gel hybridization assay. Mass cytometry was performed on patient's peripheral blood mononuclear cells, and compared with control subjects and patients with UC.The patient presented in infancy with failure to thrive and dysmorphic features, consistent with a diagnosis of dyskeratosis congenita and Hoyeraal-Hreidarsson syndrome. Severe ulcerative colitis manifested in the first year of life and proceeded to the development of a primary immunodeficiency, presenting as Pneumocystis jiroveci pneumonia and hypogammaglobulinemia. Genetic studies identified a deleterious homozygous C.3791G>A missense mutation in the helicase regulator of telomere elongation 1 (RTEL1), leading to short telomeres in the index patient. Immune repertoire studies showed polyclonal T and B cell receptor distribution, while mass cytometry analysis demonstrated marked immunological alterations, including a predominance of naïve T cells, paucity of B cells, and a decrease in various innate immune subsets.RTEL1 mutations are associated with significant alterations in immune landscape and can manifest with infantile-onset IBD. A high index of suspicion is required in Ashkenazi Jewish families where the carriage rate of the C.3791G>A variant is high.

  View details for DOI 10.1007/s10875-020-00829-z

  View details for PubMedID 32710398

• Full length RTEL1 is required for the elongation of the single-stranded telomeric overhang by telomerase. Nucleic acids research Awad, A., Glousker, G., Lamm, N., Tawil, S., Hourvitz, N., Smoom, R., Revy, P., Tzfati, Y. 2020; 48 (13): 7239-7251

  Abstract

  Telomeres cap the ends of eukaryotic chromosomes and distinguish them from broken DNA ends to suppress DNA damage response, cell cycle arrest and genomic instability. Telomeres are elongated by telomerase to compensate for incomplete replication and nuclease degradation and to extend the proliferation potential of germ and stem cells and most cancers. However, telomeres in somatic cells gradually shorten with age, ultimately leading to cellular senescence. Hoyeraal-Hreidarsson syndrome (HHS) is characterized by accelerated telomere shortening and diverse symptoms including bone marrow failure, immunodeficiency, and neurodevelopmental defects. HHS is caused by germline mutations in telomerase subunits, factors essential for its biogenesis and recruitment to telomeres, and in the helicase RTEL1. While diverse phenotypes were associated with RTEL1 deficiency, the telomeric role of RTEL1 affected in HHS is yet unknown. Inducible ectopic expression of wild-type RTEL1 in patient fibroblasts rescued the cells, enabled telomerase-dependent telomere elongation and suppressed the abnormal cellular phenotypes, while silencing its expression resulted in gradual telomere shortening. Our observations reveal an essential role of the RTEL1 C-terminus in facilitating telomerase action at the telomeric 3' overhang. Thus, the common etiology for HHS is the compromised telomerase action, resulting in telomere shortening and reduced lifespan of telomerase positive cells.

  View details for DOI 10.1093/nar/gkaa503

  View details for PubMedID 32542379

  View details for PubMedCentralID PMC7367169

• Human RTEL1 stabilizes long G-overhangs allowing telomerase-dependent over-extension. Nucleic acids research Porreca, R. M., Glousker, G., Awad, A., Matilla Fernandez, M. I., Gibaud, A., Naucke, C., Cohen, S. B., Bryan, T. M., Tzfati, Y., Draskovic, I., Londoño-Vallejo, A. 2018; 46 (9): 4533-4545

  Abstract

  Telomere maintenance protects the cell against genome instability and senescence. Accelerated telomere attrition is a characteristic of premature aging syndromes including Dyskeratosis congenita (DC). Mutations in hRTEL1 are associated with a severe form of DC called Hoyeraal-Hreidarsson syndrome (HHS). HHS patients carry short telomeres and HHS cells display telomere damage. Here we investigated how hRTEL1 contributes to telomere maintenance in human primary as well as tumor cells. Transient depletion of hRTEL1 resulted in rapid telomere shortening only in the context of telomerase-positive cells with very long telomeres and high levels of telomerase. The effect of hRTEL1 on telomere length is telomerase dependent without impacting telomerase biogenesis or targeting of the enzyme to telomeres. Instead, RTEL1 depletion led to a decrease in both G-overhang content and POT1 association with telomeres with limited telomere uncapping. Strikingly, overexpression of POT1 restored telomere length but not the overhang, demonstrating that G-overhang loss is the primary defect caused by RTEL1 depletion. We propose that hRTEL1 contributes to the maintenance of long telomeres by preserving long G-overhangs, thereby facilitating POT1 binding and elongation by telomerase.

  View details for DOI 10.1093/nar/gky173

  View details for PubMedID 29522136

  View details for PubMedCentralID PMC5961080