modified-octopus-technique-for-thoracoabdominal-aortic-aneurysm

Modified Octopus Technique for Thoracoabdominal Aortic Aneurysm

Thoracoabdominal aortic aneurysm (TAAA) involves both the thoracic and abdominal aorta and surgical treatment requires reconstructing several important ...

Hebei University

Peking University People's Hospital

Mammalian DNA double-strand breaks (DSBs) are repaired by homologous recombination (HR) and non-homologous end joining (NHEJ). HR occurs in the S/G2 phase, while NHEJ dominates in G1 phase. 53BP1 promotes NHEJ by recruiting RIF1 to DSBs in G1, but its inhibition during S/G2 remains unclear. Here, we identify DNA replication and sister chromatid cohesion 1 (DSCC1) as a key regulator that antagonizes 53BP1/RIF1 signaling in a cell-cycle-dependent manner. ATR-mediated phosphorylation of DSCC1 at Thr181 leads to its recruitment to DSB sites and promotes HR by facilitating DNA end resection. During S/G2, E2F1-induced DSCC1 expression is phosphorylated by cyclin-dependent kinase 2 (CDK2), enabling DSCC1 to interact with 53BP1 and restrain ataxia telangiectasia mutated (ATM)-mediated 53BP1 phosphorylation, consequently preventing RIF1 recruitment. Pathologically, DSCC1 is elevated in ovarian cancer, conferring poly (ADP-ribose) polymerase (PARP) inhibitor resistance. Thus, DSCC1 plays a crucial role in DSB repair pathway choice toward HR repair during S/G2 phase, providing a potential target to optimize PARP inhibitor therapy in BRCA1/2-proficient cancers.

Guo Chen

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JoVE Journal Publications

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