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  PARP1-DNA co-condensation drives DNA repair site assembly to prevent disjunction of broken DNA ends

Chappidi, N., Quail, T., Doll, S., Vogel, L. T., Aleksandrov, R., Felekyan, S., et al. (2024). PARP1-DNA co-condensation drives DNA repair site assembly to prevent disjunction of broken DNA ends. Cell, 187(4), 945-961.e18. doi:10.1016/j.cell.2024.01.015.

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 Creators:
Chappidi, Nagaraja1, Author
Quail, Thomas1, Author
Doll, Simon1, Author
Vogel, Laura T.1, Author
Aleksandrov, Radoslav1, Author
Felekyan, Suren1, Author
Kuhnemuth, Ralf1, Author
Stoynov, Stoyno1, Author
Seidel, Claus A. M.1, Author
Brugués, Jan2, Author           
Jahnel, Marcus1, Author
Franzmann, Titus M.1, Author
Alberti, Simon1, Author
Affiliations:
1external, ou_persistent22              
2Max Planck Institute for the Physics of Complex Systems, Max Planck Society, ou_2117288              

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 Abstract: DNA double-strand breaks (DSBs) are repaired at DSB sites. How DSB sites assemble and how broken DNA is prevented from separating is not understood. Here we uncover that the synapsis of broken DNA is mediated by the DSB sensor protein poly(ADP-ribose) (PAR) polymerase 1 (PARP1). Using bottom -up biochemistry, we reconstitute functional DSB sites and show that DSB sites form through co -condensation of PARP1 multimers with DNA. The co -condensates exert mechanical forces to keep DNA ends together and become enzymatically active for PAR synthesis. PARylation promotes release of PARP1 from DNA ends and the recruitment of effectors, such as Fused in Sarcoma, which stabilizes broken DNA ends against separation, revealing a finely orchestrated order of events that primes broken DNA for repair. We provide a comprehensive model for the hierarchical assembly of DSB condensates to explain DNA end synapsis and the recruitment of effector proteins for DNA damage repair.

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 Dates: 2024-02-052024-02-15
 Publication Status: Issued
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Title: Cell
Source Genre: Journal
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Publ. Info: Cambridge, Mass. : Cell Press
Pages: - Volume / Issue: 187 (4) Sequence Number: - Start / End Page: 945 - 961.e18 Identifier: ISSN: 0092-8674
CoNE: https://pure.mpg.de/cone/journals/resource/954925463183