Molecular architecture and functional dynamics of the pre-incision complex in nucleotide excision repair

Jina Yu, Chunli Yan, Tanmoy Paul, Lucas Brewer, Susan E. Tsutakawa, Chi-Lin Tsai, Samir M. Hamdan, John A. Tainer () and Ivaylo Ivanov ()
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Jina Yu: Georgia State University
Chunli Yan: Georgia State University
Tanmoy Paul: Georgia State University
Lucas Brewer: Georgia State University
Susan E. Tsutakawa: Lawrence Berkeley National Laboratory
Chi-Lin Tsai: The University of Texas MD Anderson Cancer Center
Samir M. Hamdan: King Abdullah University of Science and Technology (KAUST)
John A. Tainer: Lawrence Berkeley National Laboratory
Ivaylo Ivanov: Georgia State University

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract Nucleotide excision repair (NER) is vital for genome integrity. Yet, our understanding of the complex NER protein machinery remains incomplete. Combining cryo-EM and XL-MS data with AlphaFold2 predictions, we build an integrative model of the NER pre-incision complex(PInC). Here TFIIH serves as a molecular ruler, defining the DNA bubble size and precisely positioning the XPG and XPF nucleases for incision. Using simulations and graph theoretical analyses, we unveil PInC’s assembly, global motions, and partitioning into dynamic communities. Remarkably, XPG caps XPD’s DNA-binding groove and bridges both junctions of the DNA bubble, suggesting a novel coordination mechanism of PInC’s dual incision. XPA rigging interlaces XPF/ERCC1 with RPA, XPD, XPB, and 5′ ssDNA, exposing XPA’s crucial role in licensing the XPF/ERCC1 incision. Mapping disease mutations onto our models reveals clustering into distinct mechanistic classes, elucidating xeroderma pigmentosum and Cockayne syndrome disease etiology.

Date: 2024
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DOI: 10.1038/s41467-024-52860-y

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