PPM1D activity promotes the replication stress caused by cyclin E1 overexpression
Oncogene‐induced replication stress has been recognized as a major cause of genome instability in cancer cells. Increased expression of cyclin E1 caused by amplification of the CCNE1 gene is a common cause of replication stress in various cancers. Protein phosphatase magnesium‐dependent 1 delta (PPM...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2024-01-01
|
| Series: | Molecular Oncology |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/1878-0261.13433 |
| _version_ | 1797366085266178048 |
|---|---|
| author | Andra S. Martinikova Miroslav Stoyanov Anna Oravetzova Yannick P. Kok Shibo Yu Jana Dobrovolna Pavel Janscak Marcel vanVugt Libor Macurek |
| author_facet | Andra S. Martinikova Miroslav Stoyanov Anna Oravetzova Yannick P. Kok Shibo Yu Jana Dobrovolna Pavel Janscak Marcel vanVugt Libor Macurek |
| author_sort | Andra S. Martinikova |
| collection | DOAJ |
| description | Oncogene‐induced replication stress has been recognized as a major cause of genome instability in cancer cells. Increased expression of cyclin E1 caused by amplification of the CCNE1 gene is a common cause of replication stress in various cancers. Protein phosphatase magnesium‐dependent 1 delta (PPM1D) is a negative regulator of p53 and has been implicated in termination of the cell cycle checkpoint. Amplification of the PPM1D gene or frameshift mutations in its final exon promote tumorigenesis. Here, we show that PPM1D activity further increases the replication stress caused by overexpression of cyclin E1. In particular, we demonstrate that cells expressing a truncated mutant of PPM1D progress faster from G1 to S phase and fail to complete licensing of the replication origins. In addition, we show that transcription–replication collisions and replication fork slowing caused by CCNE1 overexpression are exaggerated in cells expressing the truncated PPM1D. Finally, replication speed and accumulation of focal DNA copy number alterations caused by induction of CCNE1 expression was rescued by pharmacological inhibition of PPM1D. We propose that increased activity of PPM1D suppresses the checkpoint function of p53 and thus promotes genome instability in cells expressing the CCNE1 oncogene. |
| first_indexed | 2024-03-08T16:58:13Z |
| format | Article |
| id | doaj.art-bca8c70888bf4c5eb9181c8b76ab63bf |
| institution | Directory Open Access Journal |
| issn | 1574-7891 1878-0261 |
| language | English |
| last_indexed | 2024-03-08T16:58:13Z |
| publishDate | 2024-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Oncology |
| spelling | doaj.art-bca8c70888bf4c5eb9181c8b76ab63bf2024-01-04T18:11:05ZengWileyMolecular Oncology1574-78911878-02612024-01-0118162010.1002/1878-0261.13433PPM1D activity promotes the replication stress caused by cyclin E1 overexpressionAndra S. Martinikova0Miroslav Stoyanov1Anna Oravetzova2Yannick P. Kok3Shibo Yu4Jana Dobrovolna5Pavel Janscak6Marcel vanVugt7Libor Macurek8Laboratory of Cancer Cell Biology, Institute of Molecular Genetics Czech Academy of Sciences Prague Czech RepublicLaboratory of Cancer Cell Biology, Institute of Molecular Genetics Czech Academy of Sciences Prague Czech RepublicLaboratory of Cancer Cell Biology, Institute of Molecular Genetics Czech Academy of Sciences Prague Czech RepublicDepartment of Medical Oncology, University Medical Center Groningen University of Groningen The NetherlandsDepartment of Pathology and Medical Biology, University Medical Center Groningen University of Groningen The NetherlandsLaboratory of Cancer Cell Biology, Institute of Molecular Genetics Czech Academy of Sciences Prague Czech RepublicLaboratory of Cancer Cell Biology, Institute of Molecular Genetics Czech Academy of Sciences Prague Czech RepublicDepartment of Medical Oncology, University Medical Center Groningen University of Groningen The NetherlandsLaboratory of Cancer Cell Biology, Institute of Molecular Genetics Czech Academy of Sciences Prague Czech RepublicOncogene‐induced replication stress has been recognized as a major cause of genome instability in cancer cells. Increased expression of cyclin E1 caused by amplification of the CCNE1 gene is a common cause of replication stress in various cancers. Protein phosphatase magnesium‐dependent 1 delta (PPM1D) is a negative regulator of p53 and has been implicated in termination of the cell cycle checkpoint. Amplification of the PPM1D gene or frameshift mutations in its final exon promote tumorigenesis. Here, we show that PPM1D activity further increases the replication stress caused by overexpression of cyclin E1. In particular, we demonstrate that cells expressing a truncated mutant of PPM1D progress faster from G1 to S phase and fail to complete licensing of the replication origins. In addition, we show that transcription–replication collisions and replication fork slowing caused by CCNE1 overexpression are exaggerated in cells expressing the truncated PPM1D. Finally, replication speed and accumulation of focal DNA copy number alterations caused by induction of CCNE1 expression was rescued by pharmacological inhibition of PPM1D. We propose that increased activity of PPM1D suppresses the checkpoint function of p53 and thus promotes genome instability in cells expressing the CCNE1 oncogene.https://doi.org/10.1002/1878-0261.13433cancercell cyclecyclin E1PPM1D phosphatasereplication stress |
| spellingShingle | Andra S. Martinikova Miroslav Stoyanov Anna Oravetzova Yannick P. Kok Shibo Yu Jana Dobrovolna Pavel Janscak Marcel vanVugt Libor Macurek PPM1D activity promotes the replication stress caused by cyclin E1 overexpression Molecular Oncology cancer cell cycle cyclin E1 PPM1D phosphatase replication stress |
| title | PPM1D activity promotes the replication stress caused by cyclin E1 overexpression |
| title_full | PPM1D activity promotes the replication stress caused by cyclin E1 overexpression |
| title_fullStr | PPM1D activity promotes the replication stress caused by cyclin E1 overexpression |
| title_full_unstemmed | PPM1D activity promotes the replication stress caused by cyclin E1 overexpression |
| title_short | PPM1D activity promotes the replication stress caused by cyclin E1 overexpression |
| title_sort | ppm1d activity promotes the replication stress caused by cyclin e1 overexpression |
| topic | cancer cell cycle cyclin E1 PPM1D phosphatase replication stress |
| url | https://doi.org/10.1002/1878-0261.13433 |
| work_keys_str_mv | AT andrasmartinikova ppm1dactivitypromotesthereplicationstresscausedbycycline1overexpression AT miroslavstoyanov ppm1dactivitypromotesthereplicationstresscausedbycycline1overexpression AT annaoravetzova ppm1dactivitypromotesthereplicationstresscausedbycycline1overexpression AT yannickpkok ppm1dactivitypromotesthereplicationstresscausedbycycline1overexpression AT shiboyu ppm1dactivitypromotesthereplicationstresscausedbycycline1overexpression AT janadobrovolna ppm1dactivitypromotesthereplicationstresscausedbycycline1overexpression AT paveljanscak ppm1dactivitypromotesthereplicationstresscausedbycycline1overexpression AT marcelvanvugt ppm1dactivitypromotesthereplicationstresscausedbycycline1overexpression AT libormacurek ppm1dactivitypromotesthereplicationstresscausedbycycline1overexpression |