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Deacetylated PCBP1 licenses PARP1 activity for DNA damage repair
Yuxin Shu1, Jun Zhang2, Linmin Zhou2
1International Cancer Center, Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Marshall Laboratory of Biomedical Engineering, Department of Biochemistry and Molecular Biology, Shenzhen University Medical School, Shenzhen 518055, China; School of Basic Medical Sciences, Wannan Medical University, Wuhu 241003, China.
Molecular Cell
|June 1, 2026
Summary
Poly (ADP-ribose) polymerase 1 (PARP1) is inhibited by poly(rC)-binding protein 1 (PCBP1) under normal conditions. SIRT7-mediated deacetylation of PCBP1 relieves this inhibition, impacting DNA repair and cancer patient survival.
Area of Science:
- Molecular Biology
- Genetics
- Biochemistry
Background:
- Poly (ADP-ribose) polymerase 1 (PARP1) is crucial for DNA damage sensing and repair, making its activity a key target for genome stability strategies.
- Controlling PARP1 activity is essential for developing effective cancer therapies, particularly those aimed at maintaining genomic integrity.
Purpose of the Study:
- To investigate the regulatory mechanism of PARP1 activity by RNA-binding proteins.
- To elucidate the role of poly(rC)-binding protein 1 (PCBP1) in modulating PARP1 function.
- To explore the therapeutic potential of targeting the PCBP1-PARP1 interaction in DNA repair and cancer treatment.
Main Methods:
- Investigated the interaction between PCBP1 and PARP1 using biochemical assays.
- Utilized cell and murine models to study the effect of PCBP1 modulation on DNA damage repair.
- Analyzed patient data to correlate PCBP1 levels with survival outcomes following radiotherapy.
- Employed gene editing and antagonistic peptides to modulate PCBP1 activity and acetylation.
Main Results:
- PCBP1 directly interacts with and inhibits PARP1 activity under physiological conditions.
- Histone deacetylase SIRT7 deacetylates PCBP1 at specific sites (K314, K351), disrupting the PCBP1-PARP1 interaction and activating PARP1.
- Modulating PCBP1 expression or acetylation impacts DNA repair efficiency in cellular and animal models.
- Reduced PCBP1 levels are linked to poorer survival rates in cancer patients undergoing radiotherapy.
Conclusions:
- PCBP1 acts as a physiological inhibitor of PARP1, with its inhibition being relieved during the early DNA damage response.
- SIRT7-mediated deacetylation of PCBP1 is a key mechanism for regulating PARP1 activation.
- PCBP1 levels and acetylation status are significant factors in DNA repair efficiency and patient prognosis after radiotherapy.
- Targeting PCBP1 deacetylation presents a potential therapeutic strategy for enhancing DNA-damaging cancer treatments.
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