Kinetic gating mechanism of DNA damage recognition by Rad4/XPC

Chen, Xuejing; Velmurugu, Yogambigai; Zheng, Guanqun; Park, Beomseok; Shim, Yoonjung; Kim, Youngchang; Liu, Lili; Van Houten, Bennett; He, Chuan; Ansari, Anjum; Min, Jung -Hyun

doi:10.1038/ncomms6849

Title: Kinetic gating mechanism of DNA damage recognition by Rad4/XPC

Journal Article · Tue Jan 06 00:00:00 EST 2015 · Nature Communications

DOI:https://doi.org/10.1038/ncomms6849· OSTI ID:1225230

Chen, Xuejing ^[1]; Velmurugu, Yogambigai ^[1]; Zheng, Guanqun ^[2]; Park, Beomseok ^[1]; Shim, Yoonjung ^[1]; Kim, Youngchang ^[3]; Liu, Lili ^[4]; Van Houten, Bennett ^[4]; He, Chuan ^[2]; Ansari, Anjum ^[1]; Min, Jung -Hyun ^[1]

Univ. of Illinois at Chicago, Chicago, IL (United States)
The Univ. of Chicago, Chicago, IL (United States)
Argonne National Lab. (ANL), Argonne, IL (United States)
Univ. of Pittsburgh, Pittsburgh, PA (United States)

The xeroderma pigmentosum C (XPC) complex initiates nucleotide excision repair by recognizing DNA lesions before recruiting downstream factors. How XPC detects structurally diverse lesions embedded within normal DNA is unknown. Here we present a crystal structure that captures the yeast XPC orthologue (Rad4) on a single register of undamaged DNA. The structure shows that a disulphide-tethered Rad4 flips out normal nucleotides and adopts a conformation similar to that seen with damaged DNA. Contrary to many DNA repair enzymes that can directly reject non-target sites as structural misfits, our results suggest that Rad4/XPC uses a kinetic gating mechanism whereby lesion selectivity arises from the kinetic competition between DNA opening and the residence time of Rad4/XPC per site. This mechanism is further supported by measurements of Rad4-induced lesion-opening times using temperature-jump perturbation spectroscopy. Lastly, kinetic gating may be a general mechanism used by site-specific DNA-binding proteins to minimize time-consuming interrogations of non-target sites.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1225230

Alternate ID(s):: OSTI ID: 1253601

Journal Information:: Nature Communications, Vol. 6; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 162 works

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