N6-Deoxyadenosine Methylation in Mammalian Mitochondrial DNA

Hao, Ziyang; Wu, Tong; Cui, Xiaolong; Zhu, Pingping; Tan, Cai‐Ping; Dou, Xiaoyang; Hsu, Kai-Wen; Lin, Yueh-Te; Peng, Pei-Hua; Zhang, Lisheng; Gao, Yawei; Hu, Lulu; Sun, Hui-Lung; Zhu, Allen; Liu, Jianzhao; Wu, Kou-Juey; He, Chuan

doi:10.1016/j.molcel.2020.02.018

Cited by 185 publications

(221 citation statements)

References 77 publications

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“…We note that numerous genome-wide studies did not produce an agreeable consensus DNA sequence containing N6mA from mammalian cells: sequences reported include TTTTT A GAAGC or TAC A [A/G]GA in mouse ES cells ( 9 , 10 ), [G/C] A GG[C/T] in a human genome (especially in the mitochondria) ( 11 ), TGG A TGGA in human glioblastoma ( 13 ), and CT[T/C/A] A TC in human mitochondria ( 21 ). From the face value of these studies, it seems that the sequences immediately before and after N6mA are both variable.…”

Section: Resultsmentioning

confidence: 99%

“…Murine MettL4 was reported to be responsible for N6mA deposition in genic elements, corresponding with transcriptional silencing ( 10 ). Interestingly, recombinant human MettL4 expressed in HEK293T cells has in vitro enzymatic activity on mitochondrial D NA ( 21 ), whereas recombinant human MettL4 expressed in E. coli has R NA MTase activity ( 29 ). The former study showed that MettL4 localizes with mitochondria in all tested tissues ( 21 ) and the latter study found mainly nuclear localization of an exogenously introduced MettL4, and failed to identify appreciable levels of N6mA in mitochondrial DNA ( 29 ).…”

Section: Discussionmentioning

confidence: 99%

“…Murine MettL4 is responsible for N6mA deposition in genic elements associated with transcriptional silencing ( 10 ). Intriguingly, recombinant human MettL4 expressed in human embryonic kidney (HEK293T) cells has in vitro enzymatic activity on mitochondrial D NA ( 21 ), whereas recombinant human MettL4 purified from Escherichia coli has R NA MTase activity ( 29 ).…”

Section: Introductionmentioning

confidence: 99%

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Biochemical and structural basis for YTH domain of human YTHDC1 binding to methylated adenine in DNA

Woodcock

Horton

Zhou

et al. 2020

Nucleic Acids Research

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The recently characterized mammalian writer (methyltransferase) and eraser (demethylase) of the DNA N6-methyladenine (N6mA) methyl mark act on single-stranded (ss) and transiently-unpaired DNA. As YTH domain-containing proteins bind N6mA-containing RNA in mammalian cells, we investigated whether mammalian YTH domains are also methyl mark readers of N6mA DNA. Here, we show that the YTH domain of YTHDC1 (known to localize in the nucleus) binds ssDNA containing N6mA, with a 10 nM dissociation constant. This binding is stronger by a factor of 5 than in an RNA context, tested under the same conditions. However, the YTH domains of YTHDF2 and YTHDF1 (predominantly cytoplasmic) exhibited the opposite effect with ∼1.5–2× stronger binding to ssRNA containing N6mA than to the corresponding DNA. We determined two structures of the YTH domain of YTHDC1 in complex with N6mA-containing ssDNA, which illustrated that YTHDC1 binds the methylated adenine in a single-stranded region flanked by duplexed DNA. We discuss the hypothesis that the writer-reader-eraser of N6mA-containining ssDNA is associated with maintaining genome stability. Structural comparison of YTH and SRA domains (the latter a DNA 5-methylcytosine reader) revealed them to be diverse members of a larger family of DNA/RNA modification readers, apparently having originated from bacterial modification-dependent restriction enzymes.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Biochemical and structural basis for YTH domain of human YTHDC1 binding to methylated adenine in DNA

Woodcock

Horton

Zhou

et al. 2020

Nucleic Acids Research

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“…However, recent studies revealed that the sample contamination, RNA contamination, technological limitations, and antibody non-specificity may cause serious problems in quantification and sequencing of 6mA in mammalian genomic DNA, casting doubts on the significance of 6mA in the mammalian genome (O’Brown et al, 2019 ; Douvlataniotis et al, 2020 ; Musheev et al, 2020 ). However, 6mA could be a regulatory mark in mammalian mitochondrial DNA (mtDNA) (Hao et al, 2020 ).…”

Section: Base-resolution Sequencing For Dna Modificationsmentioning

confidence: 99%

Mapping the epigenetic modifications of DNA and RNA

et al. 2020

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Over 17 and 160 types of chemical modifications have been identified in DNA and RNA, respectively. The interest in understanding the various biological functions of DNA and RNA modifications has lead to the cutting-edged fields of epigenomics and epitranscriptomics. Developing chemical and biological tools to detect specific modifications in the genome or transcriptome has greatly facilitated their study. Here, we review the recent technological advances in this rapidly evolving field. We focus on high-throughput detection methods and biological findings for these modifications, and discuss questions to be addressed as well. We also summarize third-generation sequencing methods, which enable long-read and single-molecule sequencing of DNA and RNA modification.

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“…These studies centered on MOMP evoke a more general feature: mitochondrial DNA, somehow in agreement with its bacterial origin, is sensed not only as an extracellular, but also as an intracellular DAMP when in the cytosol. Its relatively low methylation status, and its propensity to oxidative damage, compared to nuclear DNA, seems to be critical [99]. Numerous studies have now established that mtDNA can stimulate many Pattern Recognition Receptors (PPRs), including cGAS as mentioned above but also TLR9 and inflammasomes (reviewed in [100]) and how all these can be triggered upon MOMP remains to be elucidated.…”

Section: Momp Contributes To An Inflammatory Signaling and To Immunogmentioning

confidence: 99%

Targeting of BCL-2 Family Members during Anticancer Treatment: A Necessary Compromise between Individual Cell and Ecosystemic Responses?

2020

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The imbalance between BCL-2 homologues and pro-death counterparts frequently noted in cancer cells endows them with a cell autonomous survival advantage. To eradicate ectopic cells, inhibitors of these homologues (BH3 mimetics) were developed to trigger, during anticancer treatment, full activation of the canonical mitochondrial apoptotic pathway and related caspases. Despite efficiency in some clinical settings, these compounds do not completely fulfill their initial promise. We herein put forth that a growing body of evidence indicates that mitochondrial integrity, controlled by BCL-2 family proteins, and downstream caspases regulate other cell death modes and influence extracellular signaling by committed cells. Moreover, intercellular communications play a key role in spreading therapeutic response across cancer cell populations and in engaging an immune response. We thus advocate that BH3 mimetics administration would be more efficient in the long term if it did not induce apoptosis in all sensitive cells at the same time, but if it could instead allow (or trigger) death signal production by non-terminally committed dying cell populations. The development of such a trade-off strategy requires to unravel the effects of BH3 mimetics not only on each individual cancer cell but also on homotypic and heterotypic cell interactions in dynamic tumor ecosystems.

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N6-Deoxyadenosine Methylation in Mammalian Mitochondrial DNA

Abstract: Highlights d N 6 -methyldeoxyadenosine (6mA) is enriched in human mitochondria DNA (mtDNA) d METTL4 can mediate mammalian mtDNA 6mA methylation d mtDNA 6mA affects mitochondrial transcription, replication, and activity d The 6mA level in mtDNA is significantly elevated under hypoxic stress

Cited by 185 publications

References 77 publications

Biochemical and structural basis for YTH domain of human YTHDC1 binding to methylated adenine in DNA

Biochemical and structural basis for YTH domain of human YTHDC1 binding to methylated adenine in DNA

Mapping the epigenetic modifications of DNA and RNA

Targeting of BCL-2 Family Members during Anticancer Treatment: A Necessary Compromise between Individual Cell and Ecosystemic Responses?

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