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PARP1-dependent DNA-protein crosslink repair

ABSTRACT: DNA-protein crosslinks (DPCs) are toxic lesions that inhibit DNA related processes. Post-translational modifications (PTMs), including SUMOylation and ubiquitylation, play a central role in DPC resolution, but whether other PTMs are also involved remains elusive. Here, we identify a DPC repair pathway orchestrated by poly-ADP-ribosylation (PARylation). Using Xenopus egg extracts, we show that DPCs on single-stranded DNA gaps can be targeted for degradation via a replication-independent mechanism. During this process, DPCs are initially PARylated by PARP1 and subsequently ubiquitylated and degraded by the proteasome. Notably, PARP1-mediated DPC resolution is required for resolving topoisomerase 1-DNA cleavage complexes (TOP1ccs) induced by camptothecin. Using the Flp-nick system, we further reveal that in the absence of PARP1 activity, the TOP1cc-like lesion persists and induces replisome disassembly when encountered by a DNA replication fork. In summary, our work uncovers a PARP1-mediated DPC repair pathway that may underlie the synergistic toxicity between TOP1 poisons and PARP inhibitors.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Xenopus Laevis (african Clawed Frog)

TISSUE(S): Egg

SUBMITTER: Ivo Hendriks

LAB HEAD: Ivo Hendriks

PROVIDER: PXD043107 | Pride | 2024-08-06

REPOSITORIES: Pride

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			Action	DRS
	20200819_EXPL7_LC12_IAH_collab_ZF_Xen_C10_01.raw	Raw
	20200819_EXPL7_LC12_IAH_collab_ZF_Xen_C10_02.raw	Raw
	20200819_EXPL7_LC12_IAH_collab_ZF_Xen_C10_03.raw	Raw
	20200819_EXPL7_LC12_IAH_collab_ZF_Xen_C10_04.raw	Raw
	20200819_EXPL7_LC12_IAH_collab_ZF_Xen_C30_01.raw	Raw

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PARP1-dependent DNA-protein crosslink repair

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