Structural basis for the coiled-coil architecture of human CtIP

C. R. Morton; N. J. Rzechorzek; J. D. Maman; M. Kuramochi; H. Sekiguchi; R. Rambo; Y. C. Sasaki; O. R. Davies; L. Pellegrini

doi:10.1101/2021.03.05.434060

Structural basis for the coiled-coil architecture of human CtIP

C. R. Morton, N. J. Rzechorzek, J. D. Maman, M. Kuramochi, H. Sekiguchi, R. Rambo, Y. C. Sasaki, O. R. Davies, L. Pellegrini

Research output: Working paper

Abstract / Description of output

The DNA repair factor CtIP has a critical function in Double-Strand Break (DSB) repair by Homologous Recombination, promoting the assembly of the repair apparatus at DNA ends and participating in DNA-end resection. However, the molecular mechanisms of CtIP function in DSB repair remain unclear. Here we present an atomic model for the three-dimensional architecture of human CtIP, derived from a multi-disciplinary approach that includes X-ray crystallography, Small-angle X-ray Scattering (SAXS) and Diffracted X-ray Tracking (DXT). Our data show that CtIP adopts an extended dimer-of-dimers structure, in agreement with a role in bridging distant sites on chromosomal DNA during recombinational repair. The zinc-binding motif in CtIP’s N-terminus alters dynamically the coiled coil structure, with functional implications for the long-range interactions of CtIP with DNA. Our results provide a structural basis for the three-dimensional arrangement of chains in the CtIP tetramer, a key aspect of CtIP function in DNA DSB repair.

Original language	English
Publisher	bioRxiv, at Cold Spring Harbor Laboratory
DOIs	https://doi.org/10.1101/2021.03.05.434060
Publication status	Published - 5 Mar 2021

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title = "Structural basis for the coiled-coil architecture of human CtIP",

abstract = "The DNA repair factor CtIP has a critical function in Double-Strand Break (DSB) repair by Homologous Recombination, promoting the assembly of the repair apparatus at DNA ends and participating in DNA-end resection. However, the molecular mechanisms of CtIP function in DSB repair remain unclear. Here we present an atomic model for the three-dimensional architecture of human CtIP, derived from a multi-disciplinary approach that includes X-ray crystallography, Small-angle X-ray Scattering (SAXS) and Diffracted X-ray Tracking (DXT). Our data show that CtIP adopts an extended dimer-of-dimers structure, in agreement with a role in bridging distant sites on chromosomal DNA during recombinational repair. The zinc-binding motif in CtIP{\textquoteright}s N-terminus alters dynamically the coiled coil structure, with functional implications for the long-range interactions of CtIP with DNA. Our results provide a structural basis for the three-dimensional arrangement of chains in the CtIP tetramer, a key aspect of CtIP function in DNA DSB repair.",

author = "Morton, {C. R.} and Rzechorzek, {N. J.} and Maman, {J. D.} and M. Kuramochi and H. Sekiguchi and R. Rambo and Sasaki, {Y. C.} and Davies, {O. R.} and L. Pellegrini",

year = "2021",

month = mar,

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doi = "10.1101/2021.03.05.434060",

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T1 - Structural basis for the coiled-coil architecture of human CtIP

AU - Morton, C. R.

AU - Rzechorzek, N. J.

AU - Maman, J. D.

AU - Kuramochi, M.

AU - Sekiguchi, H.

AU - Rambo, R.

AU - Sasaki, Y. C.

AU - Davies, O. R.

AU - Pellegrini, L.

PY - 2021/3/5

Y1 - 2021/3/5

N2 - The DNA repair factor CtIP has a critical function in Double-Strand Break (DSB) repair by Homologous Recombination, promoting the assembly of the repair apparatus at DNA ends and participating in DNA-end resection. However, the molecular mechanisms of CtIP function in DSB repair remain unclear. Here we present an atomic model for the three-dimensional architecture of human CtIP, derived from a multi-disciplinary approach that includes X-ray crystallography, Small-angle X-ray Scattering (SAXS) and Diffracted X-ray Tracking (DXT). Our data show that CtIP adopts an extended dimer-of-dimers structure, in agreement with a role in bridging distant sites on chromosomal DNA during recombinational repair. The zinc-binding motif in CtIP’s N-terminus alters dynamically the coiled coil structure, with functional implications for the long-range interactions of CtIP with DNA. Our results provide a structural basis for the three-dimensional arrangement of chains in the CtIP tetramer, a key aspect of CtIP function in DNA DSB repair.

AB - The DNA repair factor CtIP has a critical function in Double-Strand Break (DSB) repair by Homologous Recombination, promoting the assembly of the repair apparatus at DNA ends and participating in DNA-end resection. However, the molecular mechanisms of CtIP function in DSB repair remain unclear. Here we present an atomic model for the three-dimensional architecture of human CtIP, derived from a multi-disciplinary approach that includes X-ray crystallography, Small-angle X-ray Scattering (SAXS) and Diffracted X-ray Tracking (DXT). Our data show that CtIP adopts an extended dimer-of-dimers structure, in agreement with a role in bridging distant sites on chromosomal DNA during recombinational repair. The zinc-binding motif in CtIP’s N-terminus alters dynamically the coiled coil structure, with functional implications for the long-range interactions of CtIP with DNA. Our results provide a structural basis for the three-dimensional arrangement of chains in the CtIP tetramer, a key aspect of CtIP function in DNA DSB repair.

U2 - 10.1101/2021.03.05.434060

DO - 10.1101/2021.03.05.434060

M3 - Working paper

BT - Structural basis for the coiled-coil architecture of human CtIP

PB - bioRxiv, at Cold Spring Harbor Laboratory

ER -

Structural basis for the coiled-coil architecture of human CtIP

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