Patient-derived C-terminal mutation of FANCI causes protein mislocalization and reveals putative EDGE motif function in DNA repair

Luca Colnaghi, Mathew J K Jones, Xiomaris M. Cotto-Rios, Detlev Schindler, Helmut Hanenberg, Tony T. Huang

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Fanconi anemia (FA) is a rare familial genome instability syndrome caused by mutations in FA genes that results in defective DNAcrosslink repair. Activation of the FA pathway requires the FA core ubiquitin ligase complex-dependent monoubiquitination of 2 interacting FA proteins, FANCI and FANCD2. Although loss of either FANCI or FANCD2 is known to prevent monoubiquitination of its respective partner, it is unclear whether FANCI has any additional domains that may be important in promoting DNA repair, independent of its monoubiquitination. Here, we focus on an FA-I patient-derived FANCI mutant protein, R1299X (deletion of 30 residues from its C-terminus), to characterize important structural region(s) in FANCI that is required to activate the FA pathway. We show that, within this short 30 amino acid stretch contains 2 separable functional signatures, a nuclear localization signal and a putative EDGE motif, that is critical for the ability of FANCI to properly monoubiquitinate FANCD2 and promote DNA crosslink resistance. Our study enable us to conclude that, although proper nuclear localization of FANCI is crucial for robust FANCD2 monoubiquitination, the putative FANCI EDGE motif is important for DNA crosslink repair.

Original languageEnglish
Pages (from-to)2247-2256
Number of pages10
JournalBlood
Volume117
Issue number7
DOIs
StatePublished - Feb 17 2011

Fingerprint

Fanconi Anemia
DNA Repair
Repair
Mutation
DNA
Fanconi Anemia Complementation Group Proteins
Genes
Proteins
Mutant Proteins
Ligases
Ubiquitin
Chemical activation
Amino Acids
Nuclear Localization Signals
Genomic Instability

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Colnaghi, L., Jones, M. J. K., Cotto-Rios, X. M., Schindler, D., Hanenberg, H., & Huang, T. T. (2011). Patient-derived C-terminal mutation of FANCI causes protein mislocalization and reveals putative EDGE motif function in DNA repair. Blood, 117(7), 2247-2256. https://doi.org/10.1182/blood-2010-07-295758

Patient-derived C-terminal mutation of FANCI causes protein mislocalization and reveals putative EDGE motif function in DNA repair. / Colnaghi, Luca; Jones, Mathew J K; Cotto-Rios, Xiomaris M.; Schindler, Detlev; Hanenberg, Helmut; Huang, Tony T.

In: Blood, Vol. 117, No. 7, 17.02.2011, p. 2247-2256.

Research output: Contribution to journalArticle

Colnaghi, L, Jones, MJK, Cotto-Rios, XM, Schindler, D, Hanenberg, H & Huang, TT 2011, 'Patient-derived C-terminal mutation of FANCI causes protein mislocalization and reveals putative EDGE motif function in DNA repair', Blood, vol. 117, no. 7, pp. 2247-2256. https://doi.org/10.1182/blood-2010-07-295758
Colnaghi, Luca ; Jones, Mathew J K ; Cotto-Rios, Xiomaris M. ; Schindler, Detlev ; Hanenberg, Helmut ; Huang, Tony T. / Patient-derived C-terminal mutation of FANCI causes protein mislocalization and reveals putative EDGE motif function in DNA repair. In: Blood. 2011 ; Vol. 117, No. 7. pp. 2247-2256.
@article{a063b8d4fd844c969f49d6f54ee1d16b,
title = "Patient-derived C-terminal mutation of FANCI causes protein mislocalization and reveals putative EDGE motif function in DNA repair",
abstract = "Fanconi anemia (FA) is a rare familial genome instability syndrome caused by mutations in FA genes that results in defective DNAcrosslink repair. Activation of the FA pathway requires the FA core ubiquitin ligase complex-dependent monoubiquitination of 2 interacting FA proteins, FANCI and FANCD2. Although loss of either FANCI or FANCD2 is known to prevent monoubiquitination of its respective partner, it is unclear whether FANCI has any additional domains that may be important in promoting DNA repair, independent of its monoubiquitination. Here, we focus on an FA-I patient-derived FANCI mutant protein, R1299X (deletion of 30 residues from its C-terminus), to characterize important structural region(s) in FANCI that is required to activate the FA pathway. We show that, within this short 30 amino acid stretch contains 2 separable functional signatures, a nuclear localization signal and a putative EDGE motif, that is critical for the ability of FANCI to properly monoubiquitinate FANCD2 and promote DNA crosslink resistance. Our study enable us to conclude that, although proper nuclear localization of FANCI is crucial for robust FANCD2 monoubiquitination, the putative FANCI EDGE motif is important for DNA crosslink repair.",
author = "Luca Colnaghi and Jones, {Mathew J K} and Cotto-Rios, {Xiomaris M.} and Detlev Schindler and Helmut Hanenberg and Huang, {Tony T.}",
year = "2011",
month = "2",
day = "17",
doi = "10.1182/blood-2010-07-295758",
language = "English",
volume = "117",
pages = "2247--2256",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "7",

}

TY - JOUR

T1 - Patient-derived C-terminal mutation of FANCI causes protein mislocalization and reveals putative EDGE motif function in DNA repair

AU - Colnaghi, Luca

AU - Jones, Mathew J K

AU - Cotto-Rios, Xiomaris M.

AU - Schindler, Detlev

AU - Hanenberg, Helmut

AU - Huang, Tony T.

PY - 2011/2/17

Y1 - 2011/2/17

N2 - Fanconi anemia (FA) is a rare familial genome instability syndrome caused by mutations in FA genes that results in defective DNAcrosslink repair. Activation of the FA pathway requires the FA core ubiquitin ligase complex-dependent monoubiquitination of 2 interacting FA proteins, FANCI and FANCD2. Although loss of either FANCI or FANCD2 is known to prevent monoubiquitination of its respective partner, it is unclear whether FANCI has any additional domains that may be important in promoting DNA repair, independent of its monoubiquitination. Here, we focus on an FA-I patient-derived FANCI mutant protein, R1299X (deletion of 30 residues from its C-terminus), to characterize important structural region(s) in FANCI that is required to activate the FA pathway. We show that, within this short 30 amino acid stretch contains 2 separable functional signatures, a nuclear localization signal and a putative EDGE motif, that is critical for the ability of FANCI to properly monoubiquitinate FANCD2 and promote DNA crosslink resistance. Our study enable us to conclude that, although proper nuclear localization of FANCI is crucial for robust FANCD2 monoubiquitination, the putative FANCI EDGE motif is important for DNA crosslink repair.

AB - Fanconi anemia (FA) is a rare familial genome instability syndrome caused by mutations in FA genes that results in defective DNAcrosslink repair. Activation of the FA pathway requires the FA core ubiquitin ligase complex-dependent monoubiquitination of 2 interacting FA proteins, FANCI and FANCD2. Although loss of either FANCI or FANCD2 is known to prevent monoubiquitination of its respective partner, it is unclear whether FANCI has any additional domains that may be important in promoting DNA repair, independent of its monoubiquitination. Here, we focus on an FA-I patient-derived FANCI mutant protein, R1299X (deletion of 30 residues from its C-terminus), to characterize important structural region(s) in FANCI that is required to activate the FA pathway. We show that, within this short 30 amino acid stretch contains 2 separable functional signatures, a nuclear localization signal and a putative EDGE motif, that is critical for the ability of FANCI to properly monoubiquitinate FANCD2 and promote DNA crosslink resistance. Our study enable us to conclude that, although proper nuclear localization of FANCI is crucial for robust FANCD2 monoubiquitination, the putative FANCI EDGE motif is important for DNA crosslink repair.

UR - http://www.scopus.com/inward/record.url?scp=79951833152&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79951833152&partnerID=8YFLogxK

U2 - 10.1182/blood-2010-07-295758

DO - 10.1182/blood-2010-07-295758

M3 - Article

C2 - 20971953

AN - SCOPUS:79951833152

VL - 117

SP - 2247

EP - 2256

JO - Blood

JF - Blood

SN - 0006-4971

IS - 7

ER -