Processing of DNA single-strand breaks with oxidatively damaged ends by LIG1

Area of Science:

• Molecular Biology
• Structural Biology
• Genetics

Background:

• DNA ligase 1 (LIG1) is crucial for sealing DNA strand breaks during replication and repair.
• Previous studies revealed LIG1's mechanisms for handling mismatches and ribonucleotides.
• The processing of oxidatively damaged DNA ends by LIG1 was not understood.

Purpose of the Study:

• To elucidate the structural mechanisms by which LIG1 processes DNA nicks with oxidative damage.
• To investigate LIG1's fidelity in the presence of oxidized bases and incorrect sugars.

Main Methods:

• Determined crystal structures of LIG1/nick DNA complexes.
• Analyzed complexes involving 3 -8-oxodG and 3 -8-oxorG.
• Examined pre- and post-catalytic steps of the ligation reaction.

Main Results:

• Observed altered distances at +1 and +2 nucleotides and template base positioning to accommodate oxidative lesions.
• Demonstrated that 8-oxoG can form Hoogsteen or Watson-Crick base pairs in syn or anti conformations.
• Showed that structural adjustments result in either mutagenic or non-mutagenic ligation outcomes.

Conclusions:

• LIG1 employs specific structural adjustments to process nicks with oxidative damage.
• The enzyme's processing of these lesions influences ligation fidelity, impacting genome integrity.
• Findings provide mechanistic insights into LIG1's role in maintaining genomic stability during DNA repair and replication.