The FANCD2-FANCI complex is recruited to DNA interstrand crosslinks before monoubiquitination of FANCD2

Chih-Chao Liang, Zhuolun Li, David Lopez-Martinez, William V. Nicholson, Catherine Vénien-Bryan, Martin A. Cohn (Lead / Corresponding author)

Research output: Contribution to journalArticle

21 Citations (Scopus)
6 Downloads (Pure)

Abstract

The Fanconi anaemia (FA) pathway is important for the repair of DNA interstrand crosslinks (ICL). The FANCD2–FANCI complex is central to the pathway, and localizes to ICLs dependent on its monoubiquitination. It has remained elusive whether the complex is recruited before or after the critical monoubiquitination. Here, we report the first structural insight into the human FANCD2–FANCI complex by obtaining the cryo-EM structure. The complex contains an inner cavity, large enough to accommodate a double-stranded DNA helix, as well as a protruding Tower domain. Disease-causing mutations in the Tower domain are observed in several FA patients. Our work reveals that recruitment of the complex to a stalled replication fork serves as the trigger for the activating monoubiquitination event. Taken together, our results uncover the mechanism of how the FANCD2–FANCI complex activates the FA pathway, and explains the underlying molecular defect in FA patients with mutations in the Tower domain.
Original languageEnglish
Article number12124
Pages (from-to)1-10
Number of pages10
JournalNature Communications
Volume7
DOIs
Publication statusPublished - 13 Jul 2016

Fingerprint

anemias
Fanconi Anemia
Towers
towers
deoxyribonucleic acid
DNA
mutations
Mutation
forks
Repair
DNA Repair
helices
Defects
actuators
cavities
defects

Cite this

Liang, Chih-Chao ; Li, Zhuolun ; Lopez-Martinez, David ; Nicholson, William V. ; Vénien-Bryan, Catherine ; Cohn, Martin A. / The FANCD2-FANCI complex is recruited to DNA interstrand crosslinks before monoubiquitination of FANCD2. In: Nature Communications. 2016 ; Vol. 7. pp. 1-10.
@article{e33a4c822df64c9080e5449605bde2bc,
title = "The FANCD2-FANCI complex is recruited to DNA interstrand crosslinks before monoubiquitination of FANCD2",
abstract = "The Fanconi anaemia (FA) pathway is important for the repair of DNA interstrand crosslinks (ICL). The FANCD2–FANCI complex is central to the pathway, and localizes to ICLs dependent on its monoubiquitination. It has remained elusive whether the complex is recruited before or after the critical monoubiquitination. Here, we report the first structural insight into the human FANCD2–FANCI complex by obtaining the cryo-EM structure. The complex contains an inner cavity, large enough to accommodate a double-stranded DNA helix, as well as a protruding Tower domain. Disease-causing mutations in the Tower domain are observed in several FA patients. Our work reveals that recruitment of the complex to a stalled replication fork serves as the trigger for the activating monoubiquitination event. Taken together, our results uncover the mechanism of how the FANCD2–FANCI complex activates the FA pathway, and explains the underlying molecular defect in FA patients with mutations in the Tower domain.",
author = "Chih-Chao Liang and Zhuolun Li and David Lopez-Martinez and Nicholson, {William V.} and Catherine V{\'e}nien-Bryan and Cohn, {Martin A.}",
year = "2016",
month = "7",
day = "13",
doi = "10.1038/ncomms12124",
language = "English",
volume = "7",
pages = "1--10",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",

}

The FANCD2-FANCI complex is recruited to DNA interstrand crosslinks before monoubiquitination of FANCD2. / Liang, Chih-Chao; Li, Zhuolun; Lopez-Martinez, David; Nicholson, William V.; Vénien-Bryan, Catherine; Cohn, Martin A. (Lead / Corresponding author).

In: Nature Communications, Vol. 7, 12124 , 13.07.2016, p. 1-10.

Research output: Contribution to journalArticle

TY - JOUR

T1 - The FANCD2-FANCI complex is recruited to DNA interstrand crosslinks before monoubiquitination of FANCD2

AU - Liang, Chih-Chao

AU - Li, Zhuolun

AU - Lopez-Martinez, David

AU - Nicholson, William V.

AU - Vénien-Bryan, Catherine

AU - Cohn, Martin A.

PY - 2016/7/13

Y1 - 2016/7/13

N2 - The Fanconi anaemia (FA) pathway is important for the repair of DNA interstrand crosslinks (ICL). The FANCD2–FANCI complex is central to the pathway, and localizes to ICLs dependent on its monoubiquitination. It has remained elusive whether the complex is recruited before or after the critical monoubiquitination. Here, we report the first structural insight into the human FANCD2–FANCI complex by obtaining the cryo-EM structure. The complex contains an inner cavity, large enough to accommodate a double-stranded DNA helix, as well as a protruding Tower domain. Disease-causing mutations in the Tower domain are observed in several FA patients. Our work reveals that recruitment of the complex to a stalled replication fork serves as the trigger for the activating monoubiquitination event. Taken together, our results uncover the mechanism of how the FANCD2–FANCI complex activates the FA pathway, and explains the underlying molecular defect in FA patients with mutations in the Tower domain.

AB - The Fanconi anaemia (FA) pathway is important for the repair of DNA interstrand crosslinks (ICL). The FANCD2–FANCI complex is central to the pathway, and localizes to ICLs dependent on its monoubiquitination. It has remained elusive whether the complex is recruited before or after the critical monoubiquitination. Here, we report the first structural insight into the human FANCD2–FANCI complex by obtaining the cryo-EM structure. The complex contains an inner cavity, large enough to accommodate a double-stranded DNA helix, as well as a protruding Tower domain. Disease-causing mutations in the Tower domain are observed in several FA patients. Our work reveals that recruitment of the complex to a stalled replication fork serves as the trigger for the activating monoubiquitination event. Taken together, our results uncover the mechanism of how the FANCD2–FANCI complex activates the FA pathway, and explains the underlying molecular defect in FA patients with mutations in the Tower domain.

UR - http://www.scopus.com/inward/record.url?eid=2-s2.0-84978901459&partnerID=MN8TOARS

U2 - 10.1038/ncomms12124

DO - 10.1038/ncomms12124

M3 - Article

VL - 7

SP - 1

EP - 10

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 12124

ER -