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Novel pathological ...
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Malinski, BartoszLinköping University,Linköpings universitet,Avdelningen för molekylär medicin och virologi,Medicinska fakulteten,Department of Biomedical and Clinical Sciences , Faculty of Medicine and Health Sciences, , Linköping 58185 , Sweden;Linköping University , Faculty of Medicine and Health Sciences, , Linköping 58185 , Sweden
(författare)
Novel pathological variants of NHP2 affect N-terminal domain flexibility, protein stability, H/ACA Ribonucleoprotein (RNP) complex formation and telomerase activity
- Artikel/kapitelEngelska2023
Förlag, utgivningsår, omfång ...
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OXFORD UNIV PRESS,2023
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printrdacarrier
Nummerbeteckningar
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LIBRIS-ID:oai:DiVA.org:liu-197569
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https://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-197569URI
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https://doi.org/10.1093/hmg/ddad114DOI
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https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-516750URI
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https://lup.lub.lu.se/record/65c7cd1e-d444-41ef-b4fb-1ac0507c717fURI
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Språk:engelska
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Sammanfattning på:engelska
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Ämneskategori:ref swepub-contenttype
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Ämneskategori:art swepub-publicationtype
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Funding Agencies|SNPamp;SEQ Technology Platform in Uppsala; Swedish Research Council; Knut and Alice Wallenberg Foundation; Clinical Genomics Uppsala (SciLifeLab)
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Telomere biology disorders (TBDs) are characterized by short telomeres, premature aging, bone marrow failure and cancer predisposition. Germline mutations in NHP2, encoding for one component of the telomerase cofactor H/ACA RNA binding complex together with Dyskerin, NOP10 and GAR1, have been previously reported in rare cases of TBDs. Here, we report two novel NHP2 variants (NHP2-A39T and NHP2-T44M) identified in a compound heterozygous patient affected by premature aging, bone marrow failure/myelodysplastic syndrome and gastric cancer. Although still able to support cell viability, both variants reduce the levels of hTR, the telomerase RNA component, and telomerase activity, expanding the panel of NHP2 pathological variants. Furthermore, both variants fail to be incorporated in the H/ACA RNA binding complex when in competition with wild-type endogenous NHP2, and the lack of incorporation causes their drastic proteasomal degradation. By RoseTTAFold prediction followed by molecular dynamics simulations, we reveal a dramatic distortion of residues 33-41, which normally position on top of the NHP2 core, as the main defect of NHP2-A39T, and high flexibility and the misplacement of the N-terminal region (residues 1-24) in NHP2-T44M and, to a lower degree, in NHP2-A39T. Because deletion of amino acids 2-24 causes a reduction in NHP2 levels only in the presence of wild-type NHP2, while deletion of amino acids 2-38 completely disrupts NHP2 stability, we propose that the two variants are mis-incorporated into the H/ACA binding complex due to the altered dynamics of the first 23 amino acids and/or the distortion of the residues 25-41 loop.
Ämnesord och genrebeteckningar
Biuppslag (personer, institutioner, konferenser, titlar ...)
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Vertemara, JacopoUniv Milano Bicocca, Italy,Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca , Milan 20126 , Italy
(författare)
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Faustini, Elena,1992-Linköping University,Linköpings universitet,Avdelningen för molekylär medicin och virologi,Medicinska fakulteten,Department of Biomedical and Clinical Sciences , Faculty of Medicine and Health Sciences, , Linköping 58185 , Sweden;Linköping University , Faculty of Medicine and Health Sciences, , Linköping 58185 , Sweden(Swepub:liu)elefa38
(författare)
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Ladenvall, Claes,PhD,1974-Uppsala University,Uppsala universitet,Institutionen för immunologi, genetik och patologi,Uppsala Univ, Sweden(Swepub:uu)clala862
(författare)
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Norberg, AnnaKlinisk genetik, Norrlands Universitetssjukhus , Umeå 75185 , Sweden,Norrland University Hospital
(författare)
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Zhang, YumingLinköping University,Linköpings universitet,Avdelningen för molekylär medicin och virologi,Medicinska fakulteten,Department of Biomedical and Clinical Sciences , Faculty of Medicine and Health Sciences, , Linköping 58185 , Sweden;Linköping University , Faculty of Medicine and Health Sciences, , Linköping 58185 , Sweden(Swepub:liu)yumzh62
(författare)
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von Castelmur, EleonoreLinköping University,Linköpings universitet,Kemi,Tekniska fakulteten,Department of Physics , Chemistry and Biology, , Linköping 58183 , Sweden;Linköping University , Chemistry and Biology, , Linköping 58183 , Sweden(Swepub:liu)elevo74
(författare)
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Baliakas, Panagiotis,1977-Uppsala University,Uppsala universitet,Cancerprecisionsmedicin,Uppsala Univ, Sweden(Swepub:uu)panba345
(författare)
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Tisi, RenataUniv Milano Bicocca, Italy,Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca , Milan 20126 , Italy
(författare)
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Cammenga, Jörg,1969-Linköping University,Lund University,Lunds universitet,Linköpings universitet,Avdelningen för kirurgi, ortopedi och onkologi,Medicinska fakulteten,Region Östergötland, Hematologiska kliniken US,Lund Univ, Sweden,Department of Biomedical and Clinical Sciences , Faculty of Medicine and Health Sciences, , Linköping 58185 , Sweden;Linköping University , Faculty of Medicine and Health Sciences, , Linköping 58185 , Sweden;Department of Laboratory Medicine, Lund University , Lund 22184 , Sweden,Avdelningen för molekylärmedicin och genterapi,Institutionen för laboratoriemedicin,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Division of Molecular Medicine and Gene Therapy,Department of Laboratory Medicine,Faculty of Medicine,LUCC: Lund University Cancer Centre,Other Strong Research Environments(Swepub:lu)stem-jrc
(författare)
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Lottersberger, Francisca,1978-Linköping University,Linköpings universitet,Avdelningen för molekylär medicin och virologi,Medicinska fakulteten,Department of Biomedical and Clinical Sciences , Faculty of Medicine and Health Sciences, , Linköping 58185 , Sweden;Linköping University , Faculty of Medicine and Health Sciences, , Linköping 58185 , Sweden(Swepub:liu)fralo26
(författare)
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Linköpings universitetAvdelningen för molekylär medicin och virologi
(creator_code:org_t)
Sammanhörande titlar
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Ingår i:Human Molecular Genetics: OXFORD UNIV PRESS32:19, s. 2901-29120964-69061460-2083
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