TY - JOUR
T1 - Genetic fusions favor tumorigenesis through degron loss in oncogenes
AU - Liu, Jing
AU - Tokheim, Collin
AU - Lee, Jonathan D.
AU - Gan, Wenjian
AU - North, Brian J.
AU - Liu, X. Shirley
AU - Pandolfi, Pier Paolo
AU - Wei, Wenyi
N1 - Funding Information:
W.W. and P.P.P. are co-founders and stockholders of the Rekindle Therapeutics. X.S.L. is a cofounder, board member, SAB member, and consultant of GV20 Oncotherapy and its subsidiaries; stockholder of BMY, TMO, WBA, ABT, ABBV, and JNJ; and received research funding from Takeda, Sanofi, and Novartis. The remaining authors declare no competing interests.
Funding Information:
We thank the Liu and Wei lab members for suggestions and comments on this work. This work was supported by R35CA253027 (to W.W.) and Breast Cancer Research Foundation BCRF-20-100 (to X.S.L.). C.T. is a Damon Runyon Fellow supported by the Damon Runyon Cancer Research Foundation (DRQ-04-20).
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - Chromosomal rearrangements can generate genetic fusions composed of two distinct gene sequences, many of which have been implicated in tumorigenesis and progression. Our study proposes a model whereby oncogenic gene fusions frequently alter the protein stability of the resulting fusion products, via exchanging protein degradation signal (degron) between gene sequences. Computational analyses of The Cancer Genome Atlas (TCGA) identify 2,406 cases of degron exchange events and reveal an enrichment of oncogene stabilization due to loss of degrons from fusion. Furthermore, we identify and experimentally validate that some recurrent fusions, such as BCR-ABL, CCDC6-RET and PML-RARA fusions, perturb protein stability by exchanging internal degrons. Likewise, we also validate that EGFR or RAF1 fusions can be stabilized by losing a computationally-predicted C-terminal degron. Thus, complementary to enhanced oncogene transcription via promoter swapping, our model of degron loss illustrates another general mechanism for recurrent fusion proteins in driving tumorigenesis.
AB - Chromosomal rearrangements can generate genetic fusions composed of two distinct gene sequences, many of which have been implicated in tumorigenesis and progression. Our study proposes a model whereby oncogenic gene fusions frequently alter the protein stability of the resulting fusion products, via exchanging protein degradation signal (degron) between gene sequences. Computational analyses of The Cancer Genome Atlas (TCGA) identify 2,406 cases of degron exchange events and reveal an enrichment of oncogene stabilization due to loss of degrons from fusion. Furthermore, we identify and experimentally validate that some recurrent fusions, such as BCR-ABL, CCDC6-RET and PML-RARA fusions, perturb protein stability by exchanging internal degrons. Likewise, we also validate that EGFR or RAF1 fusions can be stabilized by losing a computationally-predicted C-terminal degron. Thus, complementary to enhanced oncogene transcription via promoter swapping, our model of degron loss illustrates another general mechanism for recurrent fusion proteins in driving tumorigenesis.
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U2 - 10.1038/s41467-021-26871-y
DO - 10.1038/s41467-021-26871-y
M3 - Article
C2 - 34795215
AN - SCOPUS:85119429117
VL - 12
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 6704
ER -