BRCA1 tumor suppression depends on BRCT phosphoprotein binding, but not its E3 ligase activity.
Germline mutations of the breast cancer 1 (BRCA1) gene are a major cause of familial breast and ovarian cancer. The BRCA1 protein displays E3 ubiquitin ligase activity, and this enzymatic function is thought to be required for tumor suppression. To test this hypothesis, we generated mice that express an enzymatically defective Brca1. We found that this mutant Brca1 prevents tumor formation to the same degree as does wild-type Brca1 in three different genetically engineered mouse (GEM) models of cancer. In contrast, a mutation that ablates phosphoprotein recognition by the BRCA C terminus (BRCT) domains of BRCA1 elicits tumors in each of the three GEM models. Thus, BRCT phosphoprotein recognition, but not the E3 ligase activity, is required for BRCA1 tumor suppression.
Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA.
Reena
R
Shakya
Latarsha J
LJ
Reid
Colleen R
CR
Reczek
Francesca
F
Cole
Dieter
D
Egli
Chyuan-Sheng
CS
Lin
Dirk G
DG
deRooij
Steffen
S
Hirsch
Kandasamy
K
Ravi
James B
JB
Hicks
Matthias
M
Szabolcs
Maria
M
Jasin
Richard
R
Baer
Thomas
T
Ludwig
D000818:Animals; D019313:BRCA1 Protein / Q000737:chemistry / Q000378:metabolism*; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D053595:Embryonic Stem Cells / Q000378:metabolism; D019398:Genes, BRCA1; D008024:Ligands; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D054829:RING Finger Domains; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000378:metabolism
D019313:BRCA1 Protein; C486316:Bach1 protein, mouse; D050976:Basic-Leucine Zipper Transcription Factors; D008024:Ligands; D050505:Mutant Proteins; D010750:Phosphoproteins; D025521:Tumor Suppressor Proteins; C491163:Bard1 protein, mouse; D044767:Ubiquitin-Protein Ligases