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Title: Tetrameric Ctp1 coordinates DNA binding and DNA bridging in DNA double-strand-break repair

Abstract

Ctp1 (also known as CtIP or Sae2) collaborates with Mre11-Rad50-Nbs1 to initiate repair of DNA double-strand breaks (DSBs), but its functions remain enigmatic. In this paper, we report that tetrameric Schizosaccharomyces pombe Ctp1 contains multivalent DNA-binding and DNA-bridging activities. Through structural and biophysical analyses of the Ctp1 tetramer, we define the salient features of Ctp1 architecture: an N-terminal interlocking tetrameric helical dimer-of-dimers (THDD) domain and a central intrinsically disordered region (IDR) linked to C-terminal 'RHR' DNA-interaction motifs. The THDD, IDR and RHR are required for Ctp1 DNA-bridging activity in vitro, and both the THDD and RHR are required for efficient DSB repair in S. pombe. Finally, our results establish non-nucleolytic roles of Ctp1 in binding and coordination of DSB-repair intermediates and suggest that ablation of human CtIP DNA binding by truncating mutations underlie the CtIP-linked Seckel and Jawad syndromes.

Authors:
 [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1]
  1. Dept. of Health and Human Services (HHS), Research Triangle Park, NC (United States). National Inst. of Health. National Inst. of Environmental Health Sciences. Genome Integrity and Structural Biology Lab.
Publication Date:
Research Org.:
Dept. of Health and Human Services (HHS), Research Triangle Park, NC (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); National Inst. of Health (NIH) (United States)
OSTI Identifier:
1247334
Grant/Contract Number:
W-31-109-Eng-38; 1Z01ES102765; 1Z01ES021016
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Nature Structural & Molecular Biology
Additional Journal Information:
Journal Volume: 22; Journal Issue: 2; Journal ID: ISSN 1545-9993
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; DNA; Double-strand DNA breaks; X-ray crystallography

Citation Formats

Andres, Sara N., Appel, C. Denise, Westmoreland, James W., Williams, Jessica S., Nguyen, Yvonne, Robertson, Patrick D., Resnick, Michael A., and Williams, R. Scott. Tetrameric Ctp1 coordinates DNA binding and DNA bridging in DNA double-strand-break repair. United States: N. p., 2015. Web. doi:10.1038/nsmb.2945.
Andres, Sara N., Appel, C. Denise, Westmoreland, James W., Williams, Jessica S., Nguyen, Yvonne, Robertson, Patrick D., Resnick, Michael A., & Williams, R. Scott. Tetrameric Ctp1 coordinates DNA binding and DNA bridging in DNA double-strand-break repair. United States. doi:10.1038/nsmb.2945.
Andres, Sara N., Appel, C. Denise, Westmoreland, James W., Williams, Jessica S., Nguyen, Yvonne, Robertson, Patrick D., Resnick, Michael A., and Williams, R. Scott. Mon . "Tetrameric Ctp1 coordinates DNA binding and DNA bridging in DNA double-strand-break repair". United States. doi:10.1038/nsmb.2945. https://www.osti.gov/servlets/purl/1247334.
@article{osti_1247334,
title = {Tetrameric Ctp1 coordinates DNA binding and DNA bridging in DNA double-strand-break repair},
author = {Andres, Sara N. and Appel, C. Denise and Westmoreland, James W. and Williams, Jessica S. and Nguyen, Yvonne and Robertson, Patrick D. and Resnick, Michael A. and Williams, R. Scott},
abstractNote = {Ctp1 (also known as CtIP or Sae2) collaborates with Mre11-Rad50-Nbs1 to initiate repair of DNA double-strand breaks (DSBs), but its functions remain enigmatic. In this paper, we report that tetrameric Schizosaccharomyces pombe Ctp1 contains multivalent DNA-binding and DNA-bridging activities. Through structural and biophysical analyses of the Ctp1 tetramer, we define the salient features of Ctp1 architecture: an N-terminal interlocking tetrameric helical dimer-of-dimers (THDD) domain and a central intrinsically disordered region (IDR) linked to C-terminal 'RHR' DNA-interaction motifs. The THDD, IDR and RHR are required for Ctp1 DNA-bridging activity in vitro, and both the THDD and RHR are required for efficient DSB repair in S. pombe. Finally, our results establish non-nucleolytic roles of Ctp1 in binding and coordination of DSB-repair intermediates and suggest that ablation of human CtIP DNA binding by truncating mutations underlie the CtIP-linked Seckel and Jawad syndromes.},
doi = {10.1038/nsmb.2945},
journal = {Nature Structural & Molecular Biology},
number = 2,
volume = 22,
place = {United States},
year = {Mon Jan 12 00:00:00 EST 2015},
month = {Mon Jan 12 00:00:00 EST 2015}
}

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Cited by: 19 works
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