FANCL ubiquitinates β-catenin and enhances its nuclear function

Kim-Hien Dao, Michael D. Rotelli, Curtis L. Petersen, Stefanie Kaech-Petrie, Whitney D. Nelson, Jane E. Yates, Amy E. Hanlon Newell, Susan Olson, Brian Druker, Grover C. Bagby

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Bone marrow failure is a nearly universal complication of Fanconi anemia. The proteins encoded by FANC genes are involved in DNAdamage 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.

Original languageEnglish (US)
Pages (from-to)323-334
Number of pages12
JournalBlood
Volume120
Issue number2
DOIs
StatePublished - Jul 12 2012

Fingerprint

Catenins
Hematopoietic Stem Cells
Stem cells
Fanconi Anemia
Ubiquitin-Protein Ligases
Ubiquitin
Fanconi Anemia Complementation Group Proteins
Stem Cells
TCF Transcription Factors
Defects
Lymphocytes
Cyclin D1
Transcription
Lysine
Bone
Genes
Bone Marrow
Proteins

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

FANCL ubiquitinates β-catenin and enhances its nuclear function. / Dao, Kim-Hien; Rotelli, Michael D.; Petersen, Curtis L.; Kaech-Petrie, Stefanie; Nelson, Whitney D.; Yates, Jane E.; Hanlon Newell, Amy E.; Olson, Susan; Druker, Brian; Bagby, Grover C.

In: Blood, Vol. 120, No. 2, 12.07.2012, p. 323-334.

Research output: Contribution to journalArticle

Dao, Kim-Hien ; Rotelli, Michael D. ; Petersen, Curtis L. ; Kaech-Petrie, Stefanie ; Nelson, Whitney D. ; Yates, Jane E. ; Hanlon Newell, Amy E. ; Olson, Susan ; Druker, Brian ; Bagby, Grover C. / FANCL ubiquitinates β-catenin and enhances its nuclear function. In: Blood. 2012 ; Vol. 120, No. 2. pp. 323-334.
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