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Phosphoproteomics of ATR signaling in mouse testes
- Source :
- eLife, Vol 11 (2022)
- Publication Year :
- 2022
- Publisher :
- eLife Sciences Publications Ltd, 2022.
-
Abstract
- The phosphatidylinositol 3′ kinase (PI3K)‐related kinase ATR is crucial for mammalian meiosis. ATR promotes meiotic progression by coordinating key events in DNA repair, meiotic sex chromosome inactivation (MSCI), and checkpoint-dependent quality control during meiotic prophase I. Despite its central roles in meiosis, the ATR-dependent meiotic signaling network remains largely unknown. Here, we used phosphoproteomics to define ATR signaling events in testes from mice following chemical and genetic ablation of ATR signaling. Quantitative analysis of phosphoproteomes obtained after germ cell-specific genetic ablation of the ATR activating 9-1-1 complex or treatment with ATR inhibitor identified over 14,000 phosphorylation sites from testes samples, of which 401 phosphorylation sites were found to be dependent on both the 9-1-1 complex and ATR. Our analyses identified ATR-dependent phosphorylation events in crucial DNA damage signaling and DNA repair proteins including TOPBP1, SMC3, MDC1, RAD50, and SLX4. Importantly, we identified ATR and RAD1-dependent phosphorylation events in proteins involved in mRNA regulatory processes, including SETX and RANBP3, whose localization to the sex body was lost upon ATR inhibition. In addition to identifying the expected ATR-targeted S/T-Q motif, we identified enrichment of an S/T-P-X-K motif in the set of ATR-dependent events, suggesting that ATR promotes signaling via proline-directed kinase(s) during meiosis. Indeed, we found that ATR signaling is important for the proper localization of CDK2 in spermatocytes. Overall, our analysis establishes a map of ATR signaling in mouse testes and highlights potential meiotic-specific actions of ATR during prophase I progression.
- Subjects :
- Male
sex body
DNA Repair
Proteome
QH301-705.5
Morpholines
Science
Ataxia Telangiectasia Mutated Proteins
General Biochemistry, Genetics and Molecular Biology
stomatognathic system
Spermatocytes
Testis
prophase I
Animals
meiosis
RNA, Messenger
Phosphorylation
Biology (General)
General Immunology and Microbiology
General Neuroscience
General Medicine
Mice, Inbred C57BL
Pyrimidines
ATR
Medicine
biological phenomena, cell phenomena, and immunity
9-1-1
DNA Damage
Signal Transduction
Subjects
Details
- Language :
- English
- Volume :
- 11
- Database :
- OpenAIRE
- Journal :
- eLife
- Accession number :
- edsair.doi.dedup.....2b0c569bf530b4e0e948962bc5473187