期刊
ONCOTARGET
卷 7, 期 37, 页码 60005-60020出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.11088
关键词
fanconi anemia; hematopoietic stem and progenitor cells; oncogenic stress; protein arginine methyltransferase 5 (PRMT5)
资金
- National Institutes of Health (Heart, Lung and Blood Institute) [R01 HL076712]
- National Institutes of Health (National Cancer Institute) [R01 CA157537]
- Leukemia and Lymphoma Scholar award
- National Institutes of Health, Institutional Research Training T32 grant
- National Natural Science Foundation of China (NNSFC) [81470288]
The Fanconi anemia (FA) pathway is involved in DNA damage and other cellular stress responses. We have investigated the role of the FA pathway in oncogenic stress response by employing an in vivo stress-response model expressing the Gadd45 beta-luciferase transgene. Using two inducible models of oncogenic activation (LSL-K-ras(G12D) and Myc(ER)), we show that hematopoietic stem and progenitor cells (HSPCs) from mice deficient for the FA core complex components Fanca or Fancc exhibit aberrant short-lived response to oncogenic insults. Mechanistic studies reveal that FA deficiency in HSPCs impairs oncogenic stress-induced G(1) cell-cycle checkpoint, resulting from a compromised K-ras(G12D)-induced arginine methylation of p53 mediated by the protein arginine methyltransferase 5 (PRMT5). Furthermore, forced expression of PRMT5 in HSPCs from LSL-K-ras(G12D)/CreER-Fanca(-/-) mice prolongs oncogenic response and delays leukemia development in recipient mice. Our study defines an arginine methylation-dependent FA-p53 interplay that controls oncogenic stress response.
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