Structural basis for DNA damage-dependent poly(ADP-ribosyl)ation by human PARP-1

Area of Science:

• Biochemistry
• Molecular Biology
• Structural Biology

Background:

• Poly(ADP-ribose) polymerase-1 (PARP-1) is crucial for DNA damage repair.
• Its activation mechanism, linking DNA damage detection to enzymatic activity, remains unclear.
• PARP-1 possesses a modular domain structure influencing its function.

Purpose of the Study:

• To elucidate the structural mechanism of PARP-1 activation by DNA double-strand breaks.
• To understand how PARP-1 domains interact with damaged DNA.
• To reveal the conformational changes leading to PARP-1 catalytic activity.

Main Methods:

• X-ray crystallography was used to determine the structure of human PARP-1 domains bound to DNA double-strand breaks.
• Analysis of domain organization and interdomain contacts in the DNA-bound complex.

Main Results:

• PARP-1 binds DNA as a monomer.
• DNA damage induces a collapsed PARP-1 conformation through interdomain contacts (Zn1, Zn3, WGR).
• This conformation destabilizes the catalytic domain (CAT), increasing its dynamics.

Conclusions:

• The DNA-dependent activation of PARP-1 is mediated by a conformational change.
• Increased dynamics of the catalytic domain, induced by DNA binding, underlies PARP-1 activation.
• This structural insight provides a mechanistic explanation for PARP-1's role in DNA repair.