SART1 modulates poly-(ADP-ribose) chain accumulation and PARP1 chromatin localization

Area of Science:

• Molecular Biology
• Cancer Research
• Genetics

Background:

• Poly (ADP-ribose) polymerase inhibitors (PARPis) are crucial for treating cancers with homologous recombination deficiencies, particularly those with BRCA1/BRCA2 mutations.
• Understanding and overcoming resistance to PARPis necessitates the identification of novel modulators of PARP1 activity.

Purpose of the Study:

• To identify novel regulators of Poly (ADP-ribose) polymerase 1 (PARP1) activity by integrating data from multiple omics-scale screens.
• To investigate the role of the identified regulator, SART1, in PARP1 activity, DNA damage response, and sensitivity to PARP inhibitors.

Main Methods:

• Integrated data from three omics-scale screens to identify PARP1 activity modulators.
• Utilized gene silencing techniques to assess the impact of SART1 on poly-ADP ribosylation and PARP1 chromatin association.
• Investigated SART1 recruitment to chromatin post-DNA damage and its functional domains (N-terminus, RGG/RG box).

Main Results:

• Identified SART1 as a novel regulator of PARP1; SART1 silencing increases poly-ADP ribosylation and chromatin-bound PARP1.
• SART1 is recruited to chromatin after DNA damage, limiting PARP1 retention and activity; its N-terminus is sufficient for this regulation.
• SART1 silencing enhances sensitivity to ionizing radiation (IR) regardless of BRCA1 status and to PARPis specifically in BRCA1-deficient cells.

Conclusions:

• SART1 acts as a negative regulator of PARP1 activity on chromatin, particularly following DNA damage.
• The findings suggest SART1's potential clinical utility in enhancing the efficacy of PARP inhibitors, especially in BRCA1-mutated cancers.
• SART1 represents a promising therapeutic target for improving cancer treatment strategies involving PARPis.