A Meiotic Checkpoint Alters Repair Partner Bias to Permit Inter-sister Repair of Persistent DSBs
| Autor: | Andrés Aguilera, Tatiana García-Muse, María L. García-Rubio, Jolanta Polanowska, Nicola O’Reilly, Simon J. Boulton, Ulises Galindo-Diaz, Julie S. Martin |
|---|---|
| Přispěvatelé: | Universidad de Sevilla. Departamento de Genética, Cancer Research UK, Medical Research Council (UK), Wellcome Trust, European Commission, Ministerio de Economía y Competitividad (España), Consejo Superior de Investigaciones Científicas (España), Junta de Andalucía |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Model organisms DNA damage Synthetic lethality Biology Biochemistry & Proteomics DNA damage response General Biochemistry Genetics and Molecular Biology Germline Article 03 medical and health sciences 0302 clinical medicine inter-sister repair Meiosis Sister chromatids DNA double-strand breaks BRC-1 Animals DNA Breaks Double-Stranded Synaptonemal complex Caenorhabditis elegans Chemical Biology & High Throughput Genome Integrity & Repair fungi synaptonemal complex Chromosome Meiotic chromosome segregation Cell Biology Cell Cycle Checkpoints Cell biology DNA-Binding Proteins enzymes and coenzymes (carbohydrates) 030104 developmental biology Cell Cycle & Chromosomes ATR/ATM biological phenomena cell phenomena and immunity Genetics & Genomics 030217 neurology & neurosurgery Inter-sister repair Structural Biology & Biophysics DNA Damage |
| Zdroj: | Cell Reports idUS. Depósito de Investigación de la Universidad de Sevilla instname Digital.CSIC. Repositorio Institucional del CSIC |
| ISSN: | 2211-1247 |
| Popis: | Summary Accurate meiotic chromosome segregation critically depends on the formation of inter-homolog crossovers initiated by double-strand breaks (DSBs). Inaccuracies in this process can drive aneuploidy and developmental defects, but how meiotic cells are protected from unscheduled DNA breaks remains unexplored. Here we define a checkpoint response to persistent meiotic DSBs in C. elegans that phosphorylates the synaptonemal complex (SC) to switch repair partner from the homolog to the sister chromatid. A key target of this response is the core SC component SYP-1, which is phosphorylated in response to ionizing radiation (IR) or unrepaired meiotic DSBs. Failure to phosphorylate (syp-16A) or dephosphorylate (syp-16D) SYP-1 in response to DNA damage results in chromosome non-dysjunction, hyper-sensitivity to IR-induced DSBs, and synthetic lethality with loss of brc-1BRCA1. Since BRC-1 is required for inter-sister repair, these observations reveal that checkpoint-dependent SYP-1 phosphorylation safeguards the germline against persistent meiotic DSBs by channelling repair to the sister chromatid. Graphical Abstract Highlights • Meiotic DNA damage triggers phosphorylation of the synaptonemal complex (SC) • ATM-ATR kinases phosphorylate the SC in response to excessive meiotic DSBs • SC phosphorylation channels DNA repair to the sister chromatid Garcia-Muse et al. show that the checkpoint kinases ATM and ATR respond to excessive or unrepaired meiotic DSBs by phosphorylating the core synaptonemal complex, which channels repair via the sister chromatid. These findings reveal a mechanism that switches repair partner bias to protect meiotic cells from unscheduled DNA breaks. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|