A zinc linchpin motif in the MUTYH glycosylase interdomain connector is required for efficient repair of DNA damage

Lisa M. Engstrom, Megan K. Brinkmeyer, Yang Ha, Alan G. Raetz, Britt Hedman, Keith O. Hodgson, Edward I. Solomon, Sheila S. David

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Mammalian MutY glycosylases have a unique architecture that features an interdomain connector (IDC) that joins the catalytic N-terminal domain and 8-oxoguanine (OG) recognition C-terminal domain. The IDC has been shown to be a hub for interactions with protein partners involved in coordinating downstream repair events and signaling apoptosis. Herein, a previously unidentified zinc ion and its coordination by three Cys residues of the IDC region of eukaryotic MutY organisms were characterized by mutagenesis, ICP-MS, and EXAFS. In vitro kinetics and cellular assays on WT and Cys to Ser mutants have revealed an important function for zinc coordination on overall protein stability, iron-sulfur cluster insertion, and ability to mediate DNA damage repair. We propose that this "zinc linchpin" motif serves to structurally organize the IDC and coordinate the damage recognition and base excision functions of the C- and N-terminal domains.

Original languageEnglish (US)
Pages (from-to)7829-7832
Number of pages4
JournalJournal of the American Chemical Society
Volume136
Issue number22
DOIs
StatePublished - Jun 4 2014

Fingerprint

DNA Damage
Zinc
DNA
Repair
Proteins
Mutagenesis
Protein Stability
Cell death
Sulfur
DNA Repair
Assays
Iron
Ions
Apoptosis
Kinetics
mutY adenine glycosylase
8-hydroxyguanine
In Vitro Techniques

ASJC Scopus subject areas

  • Catalysis
  • Biochemistry
  • Colloid and Surface Chemistry
  • Chemistry(all)

Cite this

Engstrom, L. M., Brinkmeyer, M. K., Ha, Y., Raetz, A. G., Hedman, B., Hodgson, K. O., ... David, S. S. (2014). A zinc linchpin motif in the MUTYH glycosylase interdomain connector is required for efficient repair of DNA damage. Journal of the American Chemical Society, 136(22), 7829-7832. https://doi.org/10.1021/ja502942d

A zinc linchpin motif in the MUTYH glycosylase interdomain connector is required for efficient repair of DNA damage. / Engstrom, Lisa M.; Brinkmeyer, Megan K.; Ha, Yang; Raetz, Alan G.; Hedman, Britt; Hodgson, Keith O.; Solomon, Edward I.; David, Sheila S.

In: Journal of the American Chemical Society, Vol. 136, No. 22, 04.06.2014, p. 7829-7832.

Research output: Contribution to journalArticle

Engstrom, LM, Brinkmeyer, MK, Ha, Y, Raetz, AG, Hedman, B, Hodgson, KO, Solomon, EI & David, SS 2014, 'A zinc linchpin motif in the MUTYH glycosylase interdomain connector is required for efficient repair of DNA damage', Journal of the American Chemical Society, vol. 136, no. 22, pp. 7829-7832. https://doi.org/10.1021/ja502942d
Engstrom, Lisa M. ; Brinkmeyer, Megan K. ; Ha, Yang ; Raetz, Alan G. ; Hedman, Britt ; Hodgson, Keith O. ; Solomon, Edward I. ; David, Sheila S. / A zinc linchpin motif in the MUTYH glycosylase interdomain connector is required for efficient repair of DNA damage. In: Journal of the American Chemical Society. 2014 ; Vol. 136, No. 22. pp. 7829-7832.
@article{d8f9e66ce3ea4da78946b8f32e146ec1,
title = "A zinc linchpin motif in the MUTYH glycosylase interdomain connector is required for efficient repair of DNA damage",
abstract = "Mammalian MutY glycosylases have a unique architecture that features an interdomain connector (IDC) that joins the catalytic N-terminal domain and 8-oxoguanine (OG) recognition C-terminal domain. The IDC has been shown to be a hub for interactions with protein partners involved in coordinating downstream repair events and signaling apoptosis. Herein, a previously unidentified zinc ion and its coordination by three Cys residues of the IDC region of eukaryotic MutY organisms were characterized by mutagenesis, ICP-MS, and EXAFS. In vitro kinetics and cellular assays on WT and Cys to Ser mutants have revealed an important function for zinc coordination on overall protein stability, iron-sulfur cluster insertion, and ability to mediate DNA damage repair. We propose that this {"}zinc linchpin{"} motif serves to structurally organize the IDC and coordinate the damage recognition and base excision functions of the C- and N-terminal domains.",
author = "Engstrom, {Lisa M.} and Brinkmeyer, {Megan K.} and Yang Ha and Raetz, {Alan G.} and Britt Hedman and Hodgson, {Keith O.} and Solomon, {Edward I.} and David, {Sheila S.}",
year = "2014",
month = "6",
day = "4",
doi = "10.1021/ja502942d",
language = "English (US)",
volume = "136",
pages = "7829--7832",
journal = "Journal of the American Chemical Society",
issn = "0002-7863",
publisher = "American Chemical Society",
number = "22",

}

TY - JOUR

T1 - A zinc linchpin motif in the MUTYH glycosylase interdomain connector is required for efficient repair of DNA damage

AU - Engstrom, Lisa M.

AU - Brinkmeyer, Megan K.

AU - Ha, Yang

AU - Raetz, Alan G.

AU - Hedman, Britt

AU - Hodgson, Keith O.

AU - Solomon, Edward I.

AU - David, Sheila S.

PY - 2014/6/4

Y1 - 2014/6/4

N2 - Mammalian MutY glycosylases have a unique architecture that features an interdomain connector (IDC) that joins the catalytic N-terminal domain and 8-oxoguanine (OG) recognition C-terminal domain. The IDC has been shown to be a hub for interactions with protein partners involved in coordinating downstream repair events and signaling apoptosis. Herein, a previously unidentified zinc ion and its coordination by three Cys residues of the IDC region of eukaryotic MutY organisms were characterized by mutagenesis, ICP-MS, and EXAFS. In vitro kinetics and cellular assays on WT and Cys to Ser mutants have revealed an important function for zinc coordination on overall protein stability, iron-sulfur cluster insertion, and ability to mediate DNA damage repair. We propose that this "zinc linchpin" motif serves to structurally organize the IDC and coordinate the damage recognition and base excision functions of the C- and N-terminal domains.

AB - Mammalian MutY glycosylases have a unique architecture that features an interdomain connector (IDC) that joins the catalytic N-terminal domain and 8-oxoguanine (OG) recognition C-terminal domain. The IDC has been shown to be a hub for interactions with protein partners involved in coordinating downstream repair events and signaling apoptosis. Herein, a previously unidentified zinc ion and its coordination by three Cys residues of the IDC region of eukaryotic MutY organisms were characterized by mutagenesis, ICP-MS, and EXAFS. In vitro kinetics and cellular assays on WT and Cys to Ser mutants have revealed an important function for zinc coordination on overall protein stability, iron-sulfur cluster insertion, and ability to mediate DNA damage repair. We propose that this "zinc linchpin" motif serves to structurally organize the IDC and coordinate the damage recognition and base excision functions of the C- and N-terminal domains.

UR - http://www.scopus.com/inward/record.url?scp=84901917167&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84901917167&partnerID=8YFLogxK

U2 - 10.1021/ja502942d

DO - 10.1021/ja502942d

M3 - Article

C2 - 24841533

AN - SCOPUS:84901917167

VL - 136

SP - 7829

EP - 7832

JO - Journal of the American Chemical Society

JF - Journal of the American Chemical Society

SN - 0002-7863

IS - 22

ER -