TDP1 phosphorylation at S61 promotes Top1cc repair via the MUS81-dependent pathway during mitosis
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ABSTRACT: Topoisomerase 1 (Top1) removes supercoils from DNA during replication and transcription, is critical for mitotic progression to the G1 phase, and ensures DNA topology. Tyrosyl-DNA phosphodiesterase 1 (TDP1) mediates the removal of trapped Top1-DNA covalent complexes (Top1ccs). Here, we identify CDK1-dependent phosphorylation of TDP1 at S61 residue during mitosis. TDP1 defective for S61 phosphorylation (TDP1S61A) is trapped on the mitotic chromosomes, triggering DNA damage and mitotic defects. Moreover, we show that Top1cc repair in mitosis occurs via MUS81-dependent mitotic DNA repair mechanism. Replication stress (RS) induced by Camptothecin (CPT) or Aphidicolin (APH) leads to TDP1S61A enrichment at common fragile sites (CFSs), which over-stimulates MUS81-dependent chromatid breaks, anaphase bridges, and micronuclei, ultimately culminating in 53BP1 nuclear bodies in the G1-phase. Our findings provide a new insight into the cell cycle-dependent regulation of TDP1 dynamics forthe repair of trapped Top1ccs during mitosis that prevents genomic instability following RS.
INSTRUMENT(S): Q Exactive
ORGANISM(S): Homo Sapiens (human)
TISSUE(S): Cell Culture
SUBMITTER: Benu Brata Das
LAB HEAD: Professor Benu Brata Das
PROVIDER: PXD053309 | Pride | 2024-06-26
REPOSITORIES: Pride
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