The interaction of DNA repair factors ASCC2 and ASCC3 is affected by somatic cancer mutations
2020 | journal article. A publication with affiliation to the University of Göttingen.
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The interaction of DNA repair factors ASCC2 and ASCC3 is affected by somatic cancer mutations
Jia, J.; Absmeier, E.; Holton, N.; Pietrzyk-Brzezinska, A. J.; Hackert, P. ; Bohnsack, M. T. & Wahl, M. C. et al. (2020)
Nature Communications, 11(1). DOI: https://doi.org/10.1038/s41467-020-19221-x
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Details
- Authors
- Jia, Junqiao; Absmeier, Eva; Holton, Nicole; Pietrzyk-Brzezinska, Agnieszka J.; Hackert, Philipp ; Bohnsack, Markus T. ; Wahl, Markus C. ; Bohnsack, Katherine E.
- Abstract
- Abstract
The ASCC3 subunit of the activating signal co-integrator complex is a dual-cassette Ski2-like nucleic acid helicase that provides single-stranded DNA for alkylation damage repair by the α-ketoglutarate-dependent dioxygenase AlkBH3. Other ASCC components integrate ASCC3/AlkBH3 into a complex DNA repair pathway. We mapped and structurally analyzed interacting ASCC2 and ASCC3 regions. The ASCC3 fragment comprises a central helical domain and terminal, extended arms that clasp the compact ASCC2 unit. ASCC2–ASCC3 interfaces are evolutionarily highly conserved and comprise a large number of residues affected by somatic cancer mutations. We quantified contributions of protein regions to the ASCC2–ASCC3 interaction, observing that changes found in cancers lead to reduced ASCC2–ASCC3 affinity. Functional dissection of ASCC3 revealed similar organization and regulation as in the spliceosomal RNA helicase Brr2. Our results delineate functional regions in an important DNA repair complex and suggest possible molecular disease principles.
The DNA helicase ASCC3 is the largest subunit of the activating signal co-integrator complex (ASCC), and its DNA unwinding activity is required for the AlkBH3/ASCC-dependent DNA de-alkylation repair pathway. Here, the authors identify a minimal stable complex of the two ASCC subunits ASCC2 and ASCC3, determine the complex crystal structure and further show that cancer-related mutations at the interface between both proteins reduce ASCC2–ASCC3 affinity. - Issue Date
- 2020
- Journal
- Nature Communications
- eISSN
- 2041-1723
- Language
- English
- Sponsor
- Alexander von Humboldt-Stiftung (Alexander von Humboldt Foundation) https://doi.org/10.13039/100005156
Deutsche Forschungsgemeinschaft (German Research Foundation) https://doi.org/10.13039/501100001659
Freie Universität Berlin (Free University of Berlin) https://doi.org/10.13039/501100007537
Georg-August-Universität Göttingen (University of Göttingen) https://doi.org/10.13039/501100003385
Chinese Scholarship Council - PhD fellowship to J.J.