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
SN - 2041-1723
VL - 7
SP - 1
EP - 10
JO - Nature Communications
JF - Nature Communications
M1 - 12124
ER -
