Pathogenic PPM1D variants and their impact on DNA replication
Public support
Provider
Czech Science Foundation
Programme
Standard projects
Call for proposals
SGA0202600001
Main participants
Ústav molekulární genetiky AV ČR, v. v. i.
Contest type
VS - Public tender
Contract ID
26-21896S
Alternative language
Project name in Czech
Pathogenic PPM1D variants and their impact on DNA replication
Annotation in Czech
Upon DNA damage, cells protect genome integrity by activating ATM/ATR kinases that are master regulators of the coordinated recruitment of the repair factors to DNA lesions and of the cell cycle checkpoint. PPM1D phosphatase counteracts ATM/ATR activity at chromatin and terminates the checkpoint by inhibiting the tumor suppressor p53. We have recently identified gain-of-function mutations in the PPM1D that allow proliferation in the presence of DNA damage, promote genome instability and cellular transformation. How the C-terminally truncated PPM1D mutants escape the protein degradation remains currently unclear. Here, we aim to elucidate the mechanism of the rapid turnover of PPM1D in normal cells by the proteomic analysis of the interacting proteins with the C-terminal degron. Further, we will determine how the increased PPM1D activity affects DNA replication by targeting proteins directly at the replication forks and indirectly by suppressing p53 and other signaling pathways. This project will contribute to understanding the role of PPM1D in genomic instability and cancer.
Scientific branches
R&D category
ZV - Basic research
OECD FORD - main branch
10608 - Biochemistry and molecular biology
OECD FORD - secondary branch
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OECD FORD - another secondary branch
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CEP - equivalent branches <br>(according to the <a href="http://www.vyzkum.cz/storage/att/E6EF7938F0E854BAE520AC119FB22E8D/Prevodnik_oboru_Frascati.pdf">converter</a>)
CE - Biochemistry<br>EB - Genetics and molecular biology
Solution timeline
Realization period - beginning
Jan 1, 2026
Realization period - end
Dec 31, 2028
Project status
Z - Beginning multi-year project
Latest support payment
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Data delivery to CEP
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data delivery code
CEP26-GA0-GA-R
Data delivery date
Apr 27, 2026
Finance
Total approved costs
9,357 thou. CZK
Public financial support
9,024 thou. CZK
Other public sources
333 thou. CZK
Non public and foreign sources
0 thou. CZK