DNA mismatch repair activity of MutLα is regulated by CK2-dependent phosphorylation of MLH1 (S477)

Autores
Weßbecher, Isabel M.; Hinrichsen, Inga; Funke, Sebastian; Oellerich, Thomas; Plotz, Guido; Zeuzem, Stefan; Grus, Franz H.; Biondi, Ricardo Miguel; Brieger, Angela
Año de publicación
2018
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
MutLα, a heterodimer consisting of MLH1 and PMS2, is a key player of DNA mismatch repair (MMR), yet little is known about its regulation. In this study, we used mass spectrometry to identify phosphorylated residues within MLH1 and PMS2. The most frequently detected phosphorylated amino acid was serine 477 of MLH1. Pharmacological treatment indicates‎ that Casein kinase II (CK2) could be responsible for the phosphorylation of MLH1 at serine 477 in vivo. In vitro kinase assay verified MLH1 as a substrate of CK2. Most importantly, using in vitro MMR assay we could demonstrate that p-MLH1S477 lost MMR activity. Moreover, we found that levels of p-MLH1S477 varied during the cell cycle. In summary, we identified that phosphorylation of MLH1 by CK2 at amino acid position 477 can switch off MMR activity in vitro. Since CK2 is overexpressed in many tumors and is able to inactivate MMR, the new mechanism here described could have an important impact on tumors overactive in CK2.
Fil: Weßbecher, Isabel M.. Goethe Universitat Frankfurt; Alemania
Fil: Hinrichsen, Inga. Goethe Universitat Frankfurt; Alemania
Fil: Funke, Sebastian. Klinikum Der Johannes-gutenberg-universität Und Fachbereich Medizin; Alemania
Fil: Oellerich, Thomas. Goethe Universitat Frankfurt; Alemania
Fil: Plotz, Guido. Goethe Universitat Frankfurt; Alemania
Fil: Zeuzem, Stefan. Goethe Universitat Frankfurt; Alemania
Fil: Grus, Franz H.. Klinikum Der Johannes-gutenberg-universität Und Fachbereich Medizin; Alemania
Fil: Biondi, Ricardo Miguel. Goethe Universitat Frankfurt; Alemania. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Brieger, Angela. Goethe Universitat Frankfurt; Alemania
Materia
CK2
DNA MISMATCH REPAIR
LYNCH SYNDROME
MLH1
MUTLΑ
PHOSPHORYLATION
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/88677
Acceder
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network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling DNA mismatch repair activity of MutLα is regulated by CK2-dependent phosphorylation of MLH1 (S477)Weßbecher, Isabel M.Hinrichsen, IngaFunke, SebastianOellerich, ThomasPlotz, GuidoZeuzem, StefanGrus, Franz H.Biondi, Ricardo MiguelBrieger, AngelaCK2DNA MISMATCH REPAIRLYNCH SYNDROMEMLH1MUTLΑPHOSPHORYLATIONhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1MutLα, a heterodimer consisting of MLH1 and PMS2, is a key player of DNA mismatch repair (MMR), yet little is known about its regulation. In this study, we used mass spectrometry to identify phosphorylated residues within MLH1 and PMS2. The most frequently detected phosphorylated amino acid was serine 477 of MLH1. Pharmacological treatment indicates‎ that Casein kinase II (CK2) could be responsible for the phosphorylation of MLH1 at serine 477 in vivo. In vitro kinase assay verified MLH1 as a substrate of CK2. Most importantly, using in vitro MMR assay we could demonstrate that p-MLH1S477 lost MMR activity. Moreover, we found that levels of p-MLH1S477 varied during the cell cycle. In summary, we identified that phosphorylation of MLH1 by CK2 at amino acid position 477 can switch off MMR activity in vitro. Since CK2 is overexpressed in many tumors and is able to inactivate MMR, the new mechanism here described could have an important impact on tumors overactive in CK2.Fil: Weßbecher, Isabel M.. Goethe Universitat Frankfurt; AlemaniaFil: Hinrichsen, Inga. Goethe Universitat Frankfurt; AlemaniaFil: Funke, Sebastian. Klinikum Der Johannes-gutenberg-universität Und Fachbereich Medizin; AlemaniaFil: Oellerich, Thomas. Goethe Universitat Frankfurt; AlemaniaFil: Plotz, Guido. Goethe Universitat Frankfurt; AlemaniaFil: Zeuzem, Stefan. Goethe Universitat Frankfurt; AlemaniaFil: Grus, Franz H.. Klinikum Der Johannes-gutenberg-universität Und Fachbereich Medizin; AlemaniaFil: Biondi, Ricardo Miguel. Goethe Universitat Frankfurt; Alemania. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Brieger, Angela. Goethe Universitat Frankfurt; AlemaniaWiley-liss, Div John Wiley & Sons Inc2018-12info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/88677Weßbecher, Isabel M.; Hinrichsen, Inga; Funke, Sebastian; Oellerich, Thomas; Plotz, Guido; et al.; DNA mismatch repair activity of MutLα is regulated by CK2-dependent phosphorylation of MLH1 (S477); Wiley-liss, Div John Wiley & Sons Inc; Molecular Carcinogenesis; 57; 12; 12-2018; 1723-17340899-1987CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1002/mc.22892info:eu-repo/semantics/altIdentifier/url/https://onlinelibrary.wiley.com/doi/abs/10.1002/mc.22892info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:53:44Zoai:ri.conicet.gov.ar:11336/88677instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-03 09:53:44.621CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv DNA mismatch repair activity of MutLα is regulated by CK2-dependent phosphorylation of MLH1 (S477)
title DNA mismatch repair activity of MutLα is regulated by CK2-dependent phosphorylation of MLH1 (S477)
spellingShingle DNA mismatch repair activity of MutLα is regulated by CK2-dependent phosphorylation of MLH1 (S477)
Weßbecher, Isabel M.
CK2
DNA MISMATCH REPAIR
LYNCH SYNDROME
MLH1
MUTLΑ
PHOSPHORYLATION
title_short DNA mismatch repair activity of MutLα is regulated by CK2-dependent phosphorylation of MLH1 (S477)
title_full DNA mismatch repair activity of MutLα is regulated by CK2-dependent phosphorylation of MLH1 (S477)
title_fullStr DNA mismatch repair activity of MutLα is regulated by CK2-dependent phosphorylation of MLH1 (S477)
title_full_unstemmed DNA mismatch repair activity of MutLα is regulated by CK2-dependent phosphorylation of MLH1 (S477)
title_sort DNA mismatch repair activity of MutLα is regulated by CK2-dependent phosphorylation of MLH1 (S477)
dc.creator.none.fl_str_mv Weßbecher, Isabel M.
Hinrichsen, Inga
Funke, Sebastian
Oellerich, Thomas
Plotz, Guido
Zeuzem, Stefan
Grus, Franz H.
Biondi, Ricardo Miguel
Brieger, Angela
author Weßbecher, Isabel M.
author_facet Weßbecher, Isabel M.
Hinrichsen, Inga
Funke, Sebastian
Oellerich, Thomas
Plotz, Guido
Zeuzem, Stefan
Grus, Franz H.
Biondi, Ricardo Miguel
Brieger, Angela
author_role author
author2 Hinrichsen, Inga
Funke, Sebastian
Oellerich, Thomas
Plotz, Guido
Zeuzem, Stefan
Grus, Franz H.
Biondi, Ricardo Miguel
Brieger, Angela
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv CK2
DNA MISMATCH REPAIR
LYNCH SYNDROME
MLH1
MUTLΑ
PHOSPHORYLATION
topic CK2
DNA MISMATCH REPAIR
LYNCH SYNDROME
MLH1
MUTLΑ
PHOSPHORYLATION
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv MutLα, a heterodimer consisting of MLH1 and PMS2, is a key player of DNA mismatch repair (MMR), yet little is known about its regulation. In this study, we used mass spectrometry to identify phosphorylated residues within MLH1 and PMS2. The most frequently detected phosphorylated amino acid was serine 477 of MLH1. Pharmacological treatment indicates‎ that Casein kinase II (CK2) could be responsible for the phosphorylation of MLH1 at serine 477 in vivo. In vitro kinase assay verified MLH1 as a substrate of CK2. Most importantly, using in vitro MMR assay we could demonstrate that p-MLH1S477 lost MMR activity. Moreover, we found that levels of p-MLH1S477 varied during the cell cycle. In summary, we identified that phosphorylation of MLH1 by CK2 at amino acid position 477 can switch off MMR activity in vitro. Since CK2 is overexpressed in many tumors and is able to inactivate MMR, the new mechanism here described could have an important impact on tumors overactive in CK2.
Fil: Weßbecher, Isabel M.. Goethe Universitat Frankfurt; Alemania
Fil: Hinrichsen, Inga. Goethe Universitat Frankfurt; Alemania
Fil: Funke, Sebastian. Klinikum Der Johannes-gutenberg-universität Und Fachbereich Medizin; Alemania
Fil: Oellerich, Thomas. Goethe Universitat Frankfurt; Alemania
Fil: Plotz, Guido. Goethe Universitat Frankfurt; Alemania
Fil: Zeuzem, Stefan. Goethe Universitat Frankfurt; Alemania
Fil: Grus, Franz H.. Klinikum Der Johannes-gutenberg-universität Und Fachbereich Medizin; Alemania
Fil: Biondi, Ricardo Miguel. Goethe Universitat Frankfurt; Alemania. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Brieger, Angela. Goethe Universitat Frankfurt; Alemania
description MutLα, a heterodimer consisting of MLH1 and PMS2, is a key player of DNA mismatch repair (MMR), yet little is known about its regulation. In this study, we used mass spectrometry to identify phosphorylated residues within MLH1 and PMS2. The most frequently detected phosphorylated amino acid was serine 477 of MLH1. Pharmacological treatment indicates‎ that Casein kinase II (CK2) could be responsible for the phosphorylation of MLH1 at serine 477 in vivo. In vitro kinase assay verified MLH1 as a substrate of CK2. Most importantly, using in vitro MMR assay we could demonstrate that p-MLH1S477 lost MMR activity. Moreover, we found that levels of p-MLH1S477 varied during the cell cycle. In summary, we identified that phosphorylation of MLH1 by CK2 at amino acid position 477 can switch off MMR activity in vitro. Since CK2 is overexpressed in many tumors and is able to inactivate MMR, the new mechanism here described could have an important impact on tumors overactive in CK2.
publishDate 2018
dc.date.none.fl_str_mv 2018-12
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/88677
Weßbecher, Isabel M.; Hinrichsen, Inga; Funke, Sebastian; Oellerich, Thomas; Plotz, Guido; et al.; DNA mismatch repair activity of MutLα is regulated by CK2-dependent phosphorylation of MLH1 (S477); Wiley-liss, Div John Wiley & Sons Inc; Molecular Carcinogenesis; 57; 12; 12-2018; 1723-1734
0899-1987
CONICET Digital
CONICET
url http://hdl.handle.net/11336/88677
identifier_str_mv Weßbecher, Isabel M.; Hinrichsen, Inga; Funke, Sebastian; Oellerich, Thomas; Plotz, Guido; et al.; DNA mismatch repair activity of MutLα is regulated by CK2-dependent phosphorylation of MLH1 (S477); Wiley-liss, Div John Wiley & Sons Inc; Molecular Carcinogenesis; 57; 12; 12-2018; 1723-1734
0899-1987
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1002/mc.22892
info:eu-repo/semantics/altIdentifier/url/https://onlinelibrary.wiley.com/doi/abs/10.1002/mc.22892
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Wiley-liss, Div John Wiley & Sons Inc
publisher.none.fl_str_mv Wiley-liss, Div John Wiley & Sons Inc
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.13397

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