FANCL ubiquitinates β-catenin and enhances its nuclear function.
Bone marrow failure is a nearly universal complication of Fanconi anemia. The proteins encoded by FANC genes are involved in DNA damage responses through the formation of a multisubunit nuclear complex that facilitates the E3 ubiquitin ligase activity of FANCL. However, it is not known whether loss of E3 ubiquitin ligase activity accounts for the hematopoietic stem cell defects characteristic of Fanconi anemia. Here we provide evidence that FANCL increases the activity and expression of β-catenin, a key pluripotency factor in hematopoietic stem cells. We show that FANCL ubiquitinates β-catenin with atypical ubiquitin chain extension known to have nonproteolytic functions. Specifically, β-catenin modified with lysine-11 ubiquitin chain extension efficiently activates a lymphocyte enhancer-binding factor-T cell factor reporter. We also show that FANCL-deficient cells display diminished capacity to activate β-catenin leading to reduced transcription of Wnt-responsive targets c-Myc and Cyclin D1. Suppression of FANCL expression in normal human CD34(+) stem and progenitor cells results in fewer β-catenin active cells and inhibits expansion of multilineage progenitors. Together, these results suggest that diminished Wnt/β-catenin signaling may be an underlying molecular defect in FANCL-deficient hematopoietic stem cells leading to their accelerated loss.
Knight Cancer Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portand, OR 97239-3098, USA. daok@ohsu.edu
Kim-Hien T
KH
Dao
Michael D
MD
Rotelli
Curtis L
CL
Petersen
Stefanie
S
Kaech
Whitney D
WD
Nelson
Jane E
JE
Yates
Amy E
AE
Hanlon Newell
Susan B
SB
Olson
Brian J
BJ
Druker
Grover C
GC
Bagby
D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D019938:Cyclin D1 / Q000378:metabolism; D005199:Fanconi Anemia / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D052218:Fanconi Anemia Complementation Group C Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D052240:Fanconi Anemia Complementation Group L Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005312:Fetal Blood / Q000166:cytology / Q000378:metabolism; D057809:HEK293 Cells; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D039904:Pluripotent Stem Cells / Q000378:metabolism / Q000473:pathology; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051820:TCF Transcription Factors / Q000378:metabolism; D054875:Ubiquitination; D051176:beta Catenin / Q000737:chemistry / Q000378:metabolism*
C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; C497651:FANCC protein, human; C497652:Fancc protein, mouse; D052218:Fanconi Anemia Complementation Group C Protein; D011994:Recombinant Proteins; D051820:TCF Transcription Factors; D051176:beta Catenin; D019938:Cyclin D1; C499908:FANCL protein, human; D052240:Fanconi Anemia Complementation Group L Protein