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Novel pathological variants of NHP2 affect N-terminal domain flexibility, protein stability, H/ACA Ribonucleoprotein (RNP) complex formation and telomerase activity

Maliński, Bartosz ; Vertemara, Jacopo ; Faustini, Elena ; Ladenvall, Claes ; Norberg, Anna ; Zhang, Yuming ; Von Castelmur, Eleonore ; Baliakas, Panagiotis ; Tisi, Renata and Cammenga, Jörg LU , et al. (2023) In Human Molecular Genetics 32(19). p.2901-2912
Abstract

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.... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Human Molecular Genetics
volume
32
issue
19
pages
12 pages
publisher
Oxford University Press
external identifiers
  • pmid:37440454
  • scopus:85171900578
ISSN
0964-6906
DOI
10.1093/hmg/ddad114
language
English
LU publication?
yes
id
65c7cd1e-d444-41ef-b4fb-1ac0507c717f
date added to LUP
2023-12-18 10:22:27
date last changed
2024-04-16 22:30:53
@article{65c7cd1e-d444-41ef-b4fb-1ac0507c717f,
  abstract     = {{<p>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.</p>}},
  author       = {{Maliński, Bartosz and Vertemara, Jacopo and Faustini, Elena and Ladenvall, Claes and Norberg, Anna and Zhang, Yuming and Von Castelmur, Eleonore and Baliakas, Panagiotis and Tisi, Renata and Cammenga, Jörg and Lottersberger, Francisca}},
  issn         = {{0964-6906}},
  language     = {{eng}},
  month        = {{10}},
  number       = {{19}},
  pages        = {{2901--2912}},
  publisher    = {{Oxford University Press}},
  series       = {{Human Molecular Genetics}},
  title        = {{Novel pathological variants of NHP2 affect N-terminal domain flexibility, protein stability, H/ACA Ribonucleoprotein (RNP) complex formation and telomerase activity}},
  url          = {{http://dx.doi.org/10.1093/hmg/ddad114}},
  doi          = {{10.1093/hmg/ddad114}},
  volume       = {{32}},
  year         = {{2023}},
}