Structural basis for APE1 processing DNA damage in the nucleosome

Tyler M Weaver; Nicole M Hoitsma; Jonah J Spencer; Lokesh Gakhar; Nicholas J Schnicker; Bret D Freudenthal

doi:10.1038/s41467-022-33057-7

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Structural basis for APE1 processing DNA damage in the nucleosome

Journal article

Open access

Peer reviewed

Structural basis for APE1 processing DNA damage in the nucleosome

Tyler M Weaver, Nicole M Hoitsma, Jonah J Spencer, Lokesh Gakhar, Nicholas J Schnicker and Bret D Freudenthal

Nature communications, Vol.13(1), pp.5390-5390

09/14/2022

DOI: 10.1038/s41467-022-33057-7

PMCID: PMC9474862

PMID: 36104361

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https://doi.org/10.1038/s41467-022-33057-7View

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Abstract

Genomic DNA is continually exposed to endogenous and exogenous factors that promote DNA damage. Eukaryotic genomic DNA is packaged into nucleosomes, which present a barrier to accessing and effectively repairing DNA damage. The mechanisms by which DNA repair proteins overcome this barrier to repair DNA damage in the nucleosome and protect genomic stability is unknown. Here, we determine how the base excision repair (BER) endonuclease AP-endonuclease 1 (APE1) recognizes and cleaves DNA damage in the nucleosome. Kinetic assays determine that APE1 cleaves solvent-exposed AP sites in the nucleosome with 3 - 6 orders of magnitude higher efficiency than occluded AP sites. A cryo-electron microscopy structure of APE1 bound to a nucleosome containing a solvent-exposed AP site reveal that APE1 uses a DNA sculpting mechanism for AP site recognition, where APE1 bends the nucleosomal DNA to access the AP site. Notably, additional biochemical and structural characterization of occluded AP sites identify contacts between the nucleosomal DNA and histone octamer that prevent efficient processing of the AP site by APE1. These findings provide a rationale for the position-dependent activity of BER proteins in the nucleosome and suggests the ability of BER proteins to sculpt nucleosomal DNA drives efficient BER in chromatin.

Cryoelectron Microscopy

DNA - metabolism

DNA Damage

Endonucleases - genetics

Nucleosomes

Solvents

Details

Title: Subtitle: Structural basis for APE1 processing DNA damage in the nucleosome
Creators: Tyler M Weaver - University of Kansas Medical Center
Nicole M Hoitsma - University of Kansas Medical Center
Jonah J Spencer - University of Kansas Medical Center
Lokesh Gakhar - University of Iowa
Nicholas J Schnicker - University of Iowa
Bret D Freudenthal - University of Kansas Medical Center
Resource Type: Journal article
Publication Details: Nature communications, Vol.13(1), pp.5390-5390
DOI: 10.1038/s41467-022-33057-7
PMID: 36104361
PMCID: PMC9474862
ISSN: 2041-1723
eISSN: 2041-1723
Grant note: P30 CA168524 / NCI NIH HHS F32 GM140718 / NIGMS NIH HHS R35 GM128562 / NIGMS NIH HHS U24 GM129547 / NIGMS NIH HHS R01 ES029203 / NIEHS NIH HHS
Language: English
Date published: 09/14/2022
Academic Unit: Molecular Physiology and Biophysics; Medicine Administration
Record Identifier: 9984622758602771

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