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SETD2 maintains nuclear lamina stability to safeguard the genome

Histone methyltransferases play essential roles in the organization and function of chromatin. They are also frequently mutated in human diseases including cancer(1). One such often mutated methyltransferase, SETD2, associates co-transcriptionally with RNA polymerase II and catalyzes histone H3 lysi...

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Autores principales: Khan, Abid, Metts, James M., Collins, Lucas C., Mills, C. Allie, Li, Kelin, Brademeyer, Amanda L., Bowman, Brittany M., Major, M. Ben, Aubé, Jeffrey, Herring, Laura E., Davis, Ian J., Strahl, Brian D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10557632/
https://www.ncbi.nlm.nih.gov/pubmed/37808753
http://dx.doi.org/10.1101/2023.09.28.560032
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author Khan, Abid
Metts, James M.
Collins, Lucas C.
Mills, C. Allie
Li, Kelin
Brademeyer, Amanda L.
Bowman, Brittany M.
Major, M. Ben
Aubé, Jeffrey
Herring, Laura E.
Davis, Ian J.
Strahl, Brian D.
author_facet Khan, Abid
Metts, James M.
Collins, Lucas C.
Mills, C. Allie
Li, Kelin
Brademeyer, Amanda L.
Bowman, Brittany M.
Major, M. Ben
Aubé, Jeffrey
Herring, Laura E.
Davis, Ian J.
Strahl, Brian D.
author_sort Khan, Abid
collection PubMed
description Histone methyltransferases play essential roles in the organization and function of chromatin. They are also frequently mutated in human diseases including cancer(1). One such often mutated methyltransferase, SETD2, associates co-transcriptionally with RNA polymerase II and catalyzes histone H3 lysine 36 trimethylation (H3K36me3) – a modification that contributes to gene transcription, splicing, and DNA repair(2). While studies on SETD2 have largely focused on the consequences of its catalytic activity, the non-catalytic functions of SETD2 are largely unknown. Here we report a catalysis-independent function of SETD2 in maintaining nuclear lamina stability and genome integrity. We found that SETD2, via its intrinsically disordered N-terminus, associates with nuclear lamina proteins including lamin A/C, lamin B1, and emerin. Depletion of SETD2, or deletion of its N-terminus, resulted in widespread nuclear morphology abnormalities and genome stability defects that were reminiscent of a defective nuclear lamina. Mechanistically, the N-terminus of SETD2 facilitates the association of the mitotic kinase CDK1 with lamins, thereby promoting lamin phosphorylation and depolymerization required for nuclear envelope disassembly during mitosis. Taken together, our findings reveal an unanticipated link between the N-terminus of SETD2 and nuclear lamina organization that may underlie how SETD2 acts as a tumor suppressor.
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spelling pubmed-105576322023-10-07 SETD2 maintains nuclear lamina stability to safeguard the genome Khan, Abid Metts, James M. Collins, Lucas C. Mills, C. Allie Li, Kelin Brademeyer, Amanda L. Bowman, Brittany M. Major, M. Ben Aubé, Jeffrey Herring, Laura E. Davis, Ian J. Strahl, Brian D. bioRxiv Article Histone methyltransferases play essential roles in the organization and function of chromatin. They are also frequently mutated in human diseases including cancer(1). One such often mutated methyltransferase, SETD2, associates co-transcriptionally with RNA polymerase II and catalyzes histone H3 lysine 36 trimethylation (H3K36me3) – a modification that contributes to gene transcription, splicing, and DNA repair(2). While studies on SETD2 have largely focused on the consequences of its catalytic activity, the non-catalytic functions of SETD2 are largely unknown. Here we report a catalysis-independent function of SETD2 in maintaining nuclear lamina stability and genome integrity. We found that SETD2, via its intrinsically disordered N-terminus, associates with nuclear lamina proteins including lamin A/C, lamin B1, and emerin. Depletion of SETD2, or deletion of its N-terminus, resulted in widespread nuclear morphology abnormalities and genome stability defects that were reminiscent of a defective nuclear lamina. Mechanistically, the N-terminus of SETD2 facilitates the association of the mitotic kinase CDK1 with lamins, thereby promoting lamin phosphorylation and depolymerization required for nuclear envelope disassembly during mitosis. Taken together, our findings reveal an unanticipated link between the N-terminus of SETD2 and nuclear lamina organization that may underlie how SETD2 acts as a tumor suppressor. Cold Spring Harbor Laboratory 2023-09-28 /pmc/articles/PMC10557632/ /pubmed/37808753 http://dx.doi.org/10.1101/2023.09.28.560032 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
spellingShingle Article
Khan, Abid
Metts, James M.
Collins, Lucas C.
Mills, C. Allie
Li, Kelin
Brademeyer, Amanda L.
Bowman, Brittany M.
Major, M. Ben
Aubé, Jeffrey
Herring, Laura E.
Davis, Ian J.
Strahl, Brian D.
SETD2 maintains nuclear lamina stability to safeguard the genome
title SETD2 maintains nuclear lamina stability to safeguard the genome
title_full SETD2 maintains nuclear lamina stability to safeguard the genome
title_fullStr SETD2 maintains nuclear lamina stability to safeguard the genome
title_full_unstemmed SETD2 maintains nuclear lamina stability to safeguard the genome
title_short SETD2 maintains nuclear lamina stability to safeguard the genome
title_sort setd2 maintains nuclear lamina stability to safeguard the genome
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10557632/
https://www.ncbi.nlm.nih.gov/pubmed/37808753
http://dx.doi.org/10.1101/2023.09.28.560032
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