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

Yu, Jina; Yan, Chunli; Paul, Tanmoy; Brewer, Lucas; Tsutakawa, Susan E.; Tsai, Chi-Lin; Hamdan, Samir M.; Tainer, John A.; Ivanov, Ivaylo

doi:10.1038/s41467-024-52860-y

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

Journal Article · Tue Oct 01 04:00:00 EDT 2024 · Nature Communications

DOI:https://doi.org/10.1038/s41467-024-52860-y· OSTI ID:2479734

^[1]; Yan, Chunli ^[1]; Paul, Tanmoy ^[1]; ^[1]; ^[2]; ^[3]; ^[4]; ^[5]; ^[1]

Georgia State Univ., Atlanta, GA (United States)
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Univ. of Texas, Houston, TX (United States). MD Anderson Cancer Center
King Abdullah University of Science and Technology (KAUST), Thuwal (Saudi Arabia)
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States); Univ. of Texas, Houston, TX (United States). MD Anderson Cancer Center

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.

View Accepted Manuscript (DOE)

Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER), Biological Systems Science Division

Grant/Contract Number:: AC02-05CH11231; AC05-00OR22725

OSTI ID:: 2479734

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 15; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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