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Serine-linked PARP1 auto-modification controls PARP inhibitor response
Evgeniia Prokhorova1, Florian Zobel1, Rebecca Smith2
1Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.
Nature Communications
|July 2, 2021
Summary
Serine ADP-ribosylation (ADPr) on PARP1 is crucial for cancer drug tolerance. Specific serine sites (499, 507, 519) modified by HPF1 counteract Poly(ADP-ribose) polymerase inhibitor trapping, suggesting new therapy biomarkers.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Therapeutics
Background:
- Poly(ADP-ribose) polymerase 1 (PARP1) and PARP2 are key in DNA damage response.
- PARP inhibitors trap PARP1 on chromatin, leading to cancer cell death, especially in DNA repair-deficient cells.
- The role of specific ADP-ribosylation (ADPr) sites in counteracting PARP inhibitor trapping is not fully understood.
Purpose of the Study:
- To investigate the role of serine ADP-ribosylation in cellular responses to PARP1/PARP2 inhibitors.
- To identify specific serine residues on PARP1 critical for modulating PARP inhibitor trapping and tolerance.
- To explore the potential of serine ADPr regulators as biomarkers for PARP inhibitor therapy.
Main Methods:
- Investigated serine ADP-ribosylation in cellular responses to PARP1/PARP2 inhibitors.
- Identified key serine residues on PARP1 using biochemical and cellular assays.
- Analyzed the role of HPF1-dependent modification in counteracting PARP1 trapping.
Main Results:
- Demonstrated that serine ADP-ribosylation plays a vital role in cellular responses to PARP1/PARP2 inhibitors.
- Identified PARP1 serine residues 499, 507, and 519 as key sites whose modification counters PARP1 trapping.
- Showed that efficient HPF1-dependent modification of these sites contributes to inhibitor tolerance.
Conclusions:
- Serine ADP-ribosylation is a critical mechanism influencing PARP inhibitor efficacy.
- HPF1-dependent modification of PARP1 serine residues 499, 507, and 519 is essential for inhibitor tolerance.
- Genes encoding serine-specific ADPr regulators, HPF1 and ARH3, may serve as biomarkers for PARP1/PARP2 inhibitor therapy.
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