RESUMO
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.
Assuntos
Reparo do DNA , Poli(ADP-Ribose) Polimerase-1 , DNA/metabolismo , Quebras de DNA de Cadeia Dupla , Dano ao DNA , Poli(ADP-Ribose) Polimerase-1/genética , Poli(ADP-Ribose) Polimerase-1/metabolismo , HumanosRESUMO
We present the case of a patient with subarachnoid hemorrhage (SAH) secondary to a ruptured cerebral aneurysm and a refractory shock with high doses of vasopressors without a proven source of infection. This patient received therapy with high-volume hemofiltration plus adsorption, resolving the hemodynamic deterioration and with good neurological evolution. Our clinical case proposes that extracorporeal therapies may have a feasibility role in the management of complications of SAH.
Assuntos
Hemofiltração , Hemorragia Subaracnóidea/terapia , Hemofiltração/instrumentação , Humanos , Interleucina-6/sangue , Aneurisma Intracraniano/sangue , Aneurisma Intracraniano/complicações , Aneurisma Intracraniano/terapia , Masculino , Pessoa de Meia-Idade , Hemorragia Subaracnóidea/sangue , Hemorragia Subaracnóidea/complicaçõesRESUMO
We present the case of a patient who suffered from acute respiratory distress syndrome caused by pneumonia associated with COVID-19 and cytokine release syndrome. This patient received a high-volume hemofiltration plus adsorption, solving the hemodynamic deterioration, pulmonary infiltrates, and gas exchange. Our clinical case proposes that the extracorporeal therapies can have a role in the management of severe COVID-19.
