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Poly(ADP-ribosyl)ation of TIMELESS limits DNA replication stress and promotes stalled fork protection

Cell Rep. 2024-03; 
Julie Rageul , Natalie Lo , Amy L Phi , Jinal A Patel , Jennifer J Park , Hyungjin Kim
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Catalog Peptides TIM PBM1 wt peptide: GNLVVQNKQKKRRKKKKKVLDQAIVS(Genscript) Get A Quote

摘要

Poly(ADP-ribosyl)ation (PARylation), catalyzed mainly by poly(ADP-ribose) polymerase (PARP)1, is a key posttranslational modification involved in DNA replication and repair. Here, we report that TIMELESS (TIM), an essential scaffold of the replisome, is PARylated, which is linked to its proteolysis. TIM PARylation requires recognition of auto-modified PARP1 via two poly(ADP-ribose)-binding motifs, which primes TIM for proteasome-dependent degradation. Cells expressing the PARylation-refractory TIM mutant or under PARP inhibition accumulate TIM at DNA replication forks, causing replication stress and hyper-resection of stalled forks. Mechanistically, aberrant engagement of TIM with the replicative helicase imped... More

关键词

BRCA1/2; CP: Molecular biology; DNA replication stress; PARP1; PTUbL; TIMELESS; poly(ADP-ribosyl)ation; replication fork reversal; replisome; ubiquitin-proteasome