PMID- 26458103
OWN - NLM
STAT- MEDLINE
DCOM- 20151117
LR  - 20220331
IS  - 1476-4687 (Electronic)
IS  - 0028-0836 (Print)
IS  - 0028-0836 (Linking)
VI  - 526
IP  - 7574
DP  - 2015 Oct 22
TI  - Dynamic m(6)A mRNA methylation directs translational control of heat shock 
      response.
PG  - 591-4
LID - 10.1038/nature15377 [doi]
AB  - The most abundant mRNA post-transcriptional modification is N(6)-methyladenosine 
      (m(6)A), which has broad roles in RNA biology. In mammalian cells, the asymmetric 
      distribution of m(6)A along mRNAs results in relatively less methylation in the 
      5' untranslated region (5'UTR) compared to other regions. However, whether and 
      how 5'UTR methylation is regulated is poorly understood. Despite the crucial role 
      of the 5'UTR in translation initiation, very little is known about whether m(6)A 
      modification influences mRNA translation. Here we show that in response to heat 
      shock stress, certain adenosines within the 5'UTR of newly transcribed mRNAs are 
      preferentially methylated. We find that the dynamic 5'UTR methylation is a result 
      of stress-induced nuclear localization of YTHDF2, a well-characterized m(6)A 
      'reader'. Upon heat shock stress, the nuclear YTHDF2 preserves 5'UTR methylation 
      of stress-induced transcripts by limiting the m(6)A 'eraser' FTO from 
      demethylation. Remarkably, the increased 5'UTR methylation in the form of m(6)A 
      promotes cap-independent translation initiation, providing a mechanism for 
      selective mRNA translation under heat shock stress. Using Hsp70 mRNA as an 
      example, we demonstrate that a single m(6)A modification site in the 5'UTR 
      enables translation initiation independent of the 5' end N(7)-methylguanosine 
      cap. The elucidation of the dynamic features of 5'UTR methylation and its 
      critical role in cap-independent translation not only expands the breadth of 
      physiological roles of m(6)A, but also uncovers a previously unappreciated 
      translational control mechanism in heat shock response.
FAU - Zhou, Jun
AU  - Zhou J
AD  - Division of Nutritional Sciences, Cornell University, Ithaca, New York 14853, 
      USA.
FAU - Wan, Ji
AU  - Wan J
AD  - Division of Nutritional Sciences, Cornell University, Ithaca, New York 14853, 
      USA.
FAU - Gao, Xiangwei
AU  - Gao X
AD  - Division of Nutritional Sciences, Cornell University, Ithaca, New York 14853, 
      USA.
FAU - Zhang, Xingqian
AU  - Zhang X
AD  - Division of Nutritional Sciences, Cornell University, Ithaca, New York 14853, 
      USA.
FAU - Jaffrey, Samie R
AU  - Jaffrey SR
AD  - Department of Pharmacology, Weill Cornell Medical College, Cornell University, 
      New York City, New York 10065, USA.
FAU - Qian, Shu-Bing
AU  - Qian SB
AD  - Division of Nutritional Sciences, Cornell University, Ithaca, New York 14853, 
      USA.
LA  - eng
SI  - SRA/SRA280261
GR  - DA037150/DA/NIDA NIH HHS/United States
GR  - R01AG042400/AG/NIA NIH HHS/United States
GR  - R01 CA186702/CA/NCI NIH HHS/United States
GR  - DP2 OD006449/OD/NIH HHS/United States
GR  - DP2OD006449/OD/NIH HHS/United States
GR  - R01 AG042400/AG/NIA NIH HHS/United States
GR  - R01 DA037150/DA/NIDA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20151012
PL  - England
TA  - Nature
JT  - Nature
JID - 0410462
RN  - 0 (5' Untranslated Regions)
RN  - 0 (HSP70 Heat-Shock Proteins)
RN  - 0 (RNA Caps)
RN  - 0 (RNA, Messenger)
RN  - 0 (RNA-Binding Proteins)
RN  - 0 (YTHDF2 protein, mouse)
RN  - CLE6G00625 (N-methyladenosine)
RN  - EC 1.- (Mixed Function Oxygenases)
RN  - EC 1.14.11.- (FTO protein, mouse)
RN  - EC 1.14.11.33 (Alpha-Ketoglutarate-Dependent Dioxygenase FTO)
RN  - EC 4.1.3.- (Oxo-Acid-Lyases)
RN  - K72T3FS567 (Adenosine)
SB  - IM
MH  - 5' Untranslated Regions/genetics
MH  - Adenosine/*analogs & derivatives/metabolism
MH  - Alpha-Ketoglutarate-Dependent Dioxygenase FTO
MH  - Animals
MH  - Cell Line
MH  - Cell Nucleus/metabolism
MH  - Fibroblasts/cytology/metabolism
MH  - *Gene Expression Regulation
MH  - HSP70 Heat-Shock Proteins/genetics
MH  - *Heat-Shock Response/genetics
MH  - *Methylation
MH  - Mice
MH  - Mixed Function Oxygenases/antagonists & inhibitors/metabolism
MH  - Oxo-Acid-Lyases/antagonists & inhibitors/metabolism
MH  - *Peptide Chain Initiation, Translational
MH  - RNA Caps/metabolism
MH  - RNA, Messenger/genetics/*metabolism
MH  - RNA-Binding Proteins/metabolism
MH  - Transcription, Genetic/genetics
PMC - PMC4851248
MID - NIHMS712495
EDAT- 2015/10/13 06:00
MHDA- 2015/11/18 06:00
PMCR- 2016/04/29
CRDT- 2015/10/13 06:00
PHST- 2015/02/23 00:00 [received]
PHST- 2015/07/30 00:00 [accepted]
PHST- 2015/10/13 06:00 [entrez]
PHST- 2015/10/13 06:00 [pubmed]
PHST- 2015/11/18 06:00 [medline]
PHST- 2016/04/29 00:00 [pmc-release]
AID - nature15377 [pii]
AID - 10.1038/nature15377 [doi]
PST - ppublish
SO  - Nature. 2015 Oct 22;526(7574):591-4. doi: 10.1038/nature15377. Epub 2015 Oct 12.