Tankyrases Promote Homologous Recombination and Check Point Activation in Response to DSBs

Area of Science:

• Molecular Biology
• Cell Biology
• Genetics

Background:

• DNA damage response (DDR) is crucial for maintaining genomic stability.
• Mediator of DNA damage Checkpoint protein 1 (MDC1) is a key scaffold protein in the DDR pathway, essential for signaling amplification around Double Strand Breaks (DSBs).
• MDC1 plays roles in both Non-Homologous End Joining (NHEJ) and Homologous Recombination (HR) DNA repair pathways.

Purpose of the Study:

• To identify novel binding partners of MDC1.
• To investigate the role of these new partners in the DNA damage response and repair.

Main Methods:

• Co-immunoprecipitation assays to identify MDC1 binding partners.
• Immunofluorescence microscopy to visualize protein recruitment to DNA lesions.
• Assays to assess DNA end resection, BRCA1A complex stabilization, and checkpoint activation.

Main Results:

• Identified poly (ADP-ribose) Polymerases (PARPs) TNKS1 and TNKS2 as novel binding partners of MDC1.
• Demonstrated that TNKS1/2 are recruited to DNA lesions by MDC1.
• Showed that TNKS1/2 regulate DNA end resection and BRCA1A complex stabilization at DSBs.

Conclusions:

• MDC1 interacts with TNKS1/2, facilitating their recruitment to DNA damage sites.
• The MDC1-TNKS interaction is critical for efficient Double Strand Break repair through Homologous Recombination (HR).
• This interaction also contributes to proper DNA damage checkpoint activation, highlighting a new regulatory mechanism in DNA repair.