Thymine DNA glycosylase is essential for active DNA demethylation by linked deamination-base excision repair

Salvatore Cortellino; Jinfei Xu; Mara Sannai; Robert Moore; Elena Caretti; Antonio Cigliano; Madeleine Le Coz; Karthik Devarajan; Andy Wessels; Dianne Soprano; Lara K. Abramowitz; Marisa S. Bartolomei; Florian Rambow; Maria Rosaria Bassi; Tiziana Bruno; Maurizio Fanciulli; Catherine Renner; Andres J. Klein-Szanto; Yoshihiro Matsumoto; Dominique Kobi; Irwin Davidson; Christophe Alberti; Lionel Larue; Alfonso Bellacosa

doi:10.1016/j.cell.2011.06.020

Thymine DNA glycosylase is essential for active DNA demethylation by linked deamination-base excision repair

Salvatore Cortellino, Jinfei Xu, Mara Sannai, Robert Moore, Elena Caretti, Antonio Cigliano, Madeleine Le Coz, Karthik Devarajan, Andy Wessels, Dianne Soprano, Lara K. Abramowitz, Marisa S. Bartolomei, Florian Rambow, Maria Rosaria Bassi, Tiziana Bruno, Maurizio Fanciulli, Catherine Renner, Andres J. Klein-Szanto, Yoshihiro Matsumoto, Dominique KobiIrwin Davidson, Christophe Alberti, Lionel Larue, Alfonso Bellacosa

Research output: Contribution to journal › Article › peer-review

659 Scopus citations

Abstract

DNA methylation is a major epigenetic mechanism for gene silencing. Whereas methyltransferases mediate cytosine methylation, it is less clear how unmethylated regions in mammalian genomes are protected from de novo methylation and whether an active demethylating activity is involved. Here, we show that either knockout or catalytic inactivation of the DNA repair enzyme thymine DNA glycosylase (TDG) leads to embryonic lethality in mice. TDG is necessary for recruiting p300 to retinoic acid (RA)-regulated promoters, protection of CpG islands from hypermethylation, and active demethylation of tissue-specific developmentally and hormonally regulated promoters and enhancers. TDG interacts with the deaminase AID and the damage response protein GADD45a. These findings highlight a dual role for TDG in promoting proper epigenetic states during development and suggest a two-step mechanism for DNA demethylation in mammals, whereby 5-methylcytosine and 5-hydroxymethylcytosine are first deaminated by AID to thymine and 5-hydroxymethyluracil, respectively, followed by TDG-mediated thymine and 5-hydroxymethyluracil excision repair. PaperClip:

Original language	English
Pages (from-to)	67-79
Number of pages	13
Journal	Cell
Volume	146
Issue number	1
DOIs	https://doi.org/10.1016/j.cell.2011.06.020
State	Published - Jul 8 2011

Keywords

5-Methylcytosine/metabolism
Animals
Cell Cycle Proteins/metabolism
Cytidine Deaminase/metabolism
Cytosine/analogs & derivatives
DNA Methylation
Embryonic Development
Female
Gene Expression Regulation, Developmental
Gene Knock-In Techniques
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Nuclear Proteins/metabolism
Promoter Regions, Genetic
Thymine DNA Glycosylase/genetics
Transcription, Genetic

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10.1016/j.cell.2011.06.020

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Cortellino, S., Xu, J., Sannai, M., Moore, R., Caretti, E., Cigliano, A., Le Coz, M., Devarajan, K., Wessels, A., Soprano, D., Abramowitz, L. K., Bartolomei, M. S., Rambow, F., Bassi, M. R., Bruno, T., Fanciulli, M., Renner, C., Klein-Szanto, A. J., Matsumoto, Y., ... Bellacosa, A. (2011). Thymine DNA glycosylase is essential for active DNA demethylation by linked deamination-base excision repair. Cell, 146(1), 67-79. https://doi.org/10.1016/j.cell.2011.06.020

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title = "Thymine DNA glycosylase is essential for active DNA demethylation by linked deamination-base excision repair",

abstract = "DNA methylation is a major epigenetic mechanism for gene silencing. Whereas methyltransferases mediate cytosine methylation, it is less clear how unmethylated regions in mammalian genomes are protected from de novo methylation and whether an active demethylating activity is involved. Here, we show that either knockout or catalytic inactivation of the DNA repair enzyme thymine DNA glycosylase (TDG) leads to embryonic lethality in mice. TDG is necessary for recruiting p300 to retinoic acid (RA)-regulated promoters, protection of CpG islands from hypermethylation, and active demethylation of tissue-specific developmentally and hormonally regulated promoters and enhancers. TDG interacts with the deaminase AID and the damage response protein GADD45a. These findings highlight a dual role for TDG in promoting proper epigenetic states during development and suggest a two-step mechanism for DNA demethylation in mammals, whereby 5-methylcytosine and 5-hydroxymethylcytosine are first deaminated by AID to thymine and 5-hydroxymethyluracil, respectively, followed by TDG-mediated thymine and 5-hydroxymethyluracil excision repair. PaperClip:",

keywords = "5-Methylcytosine/metabolism, Animals, Cell Cycle Proteins/metabolism, Cytidine Deaminase/metabolism, Cytosine/analogs & derivatives, DNA Methylation, Embryonic Development, Female, Gene Expression Regulation, Developmental, Gene Knock-In Techniques, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Nuclear Proteins/metabolism, Promoter Regions, Genetic, Thymine DNA Glycosylase/genetics, Transcription, Genetic",

author = "Salvatore Cortellino and Jinfei Xu and Mara Sannai and Robert Moore and Elena Caretti and Antonio Cigliano and {Le Coz}, Madeleine and Karthik Devarajan and Andy Wessels and Dianne Soprano and Abramowitz, {Lara K.} and Bartolomei, {Marisa S.} and Florian Rambow and Bassi, {Maria Rosaria} and Tiziana Bruno and Maurizio Fanciulli and Catherine Renner and Klein-Szanto, {Andres J.} and Yoshihiro Matsumoto and Dominique Kobi and Irwin Davidson and Christophe Alberti and Lionel Larue and Alfonso Bellacosa",

year = "2011",

month = jul,

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doi = "10.1016/j.cell.2011.06.020",

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Cortellino, S, Xu, J, Sannai, M, Moore, R, Caretti, E, Cigliano, A, Le Coz, M, Devarajan, K, Wessels, A, Soprano, D, Abramowitz, LK, Bartolomei, MS, Rambow, F, Bassi, MR, Bruno, T, Fanciulli, M, Renner, C, Klein-Szanto, AJ, Matsumoto, Y, Kobi, D, Davidson, I, Alberti, C, Larue, L & Bellacosa, A 2011, 'Thymine DNA glycosylase is essential for active DNA demethylation by linked deamination-base excision repair', Cell, vol. 146, no. 1, pp. 67-79. https://doi.org/10.1016/j.cell.2011.06.020

TY - JOUR

T1 - Thymine DNA glycosylase is essential for active DNA demethylation by linked deamination-base excision repair

AU - Cortellino, Salvatore

AU - Xu, Jinfei

AU - Sannai, Mara

AU - Moore, Robert

AU - Caretti, Elena

AU - Cigliano, Antonio

AU - Le Coz, Madeleine

AU - Devarajan, Karthik

AU - Wessels, Andy

AU - Soprano, Dianne

AU - Abramowitz, Lara K.

AU - Bartolomei, Marisa S.

AU - Rambow, Florian

AU - Bassi, Maria Rosaria

AU - Bruno, Tiziana

AU - Fanciulli, Maurizio

AU - Renner, Catherine

AU - Klein-Szanto, Andres J.

AU - Matsumoto, Yoshihiro

AU - Kobi, Dominique

AU - Davidson, Irwin

AU - Alberti, Christophe

AU - Larue, Lionel

AU - Bellacosa, Alfonso

PY - 2011/7/8

Y1 - 2011/7/8

N2 - DNA methylation is a major epigenetic mechanism for gene silencing. Whereas methyltransferases mediate cytosine methylation, it is less clear how unmethylated regions in mammalian genomes are protected from de novo methylation and whether an active demethylating activity is involved. Here, we show that either knockout or catalytic inactivation of the DNA repair enzyme thymine DNA glycosylase (TDG) leads to embryonic lethality in mice. TDG is necessary for recruiting p300 to retinoic acid (RA)-regulated promoters, protection of CpG islands from hypermethylation, and active demethylation of tissue-specific developmentally and hormonally regulated promoters and enhancers. TDG interacts with the deaminase AID and the damage response protein GADD45a. These findings highlight a dual role for TDG in promoting proper epigenetic states during development and suggest a two-step mechanism for DNA demethylation in mammals, whereby 5-methylcytosine and 5-hydroxymethylcytosine are first deaminated by AID to thymine and 5-hydroxymethyluracil, respectively, followed by TDG-mediated thymine and 5-hydroxymethyluracil excision repair. PaperClip:

AB - DNA methylation is a major epigenetic mechanism for gene silencing. Whereas methyltransferases mediate cytosine methylation, it is less clear how unmethylated regions in mammalian genomes are protected from de novo methylation and whether an active demethylating activity is involved. Here, we show that either knockout or catalytic inactivation of the DNA repair enzyme thymine DNA glycosylase (TDG) leads to embryonic lethality in mice. TDG is necessary for recruiting p300 to retinoic acid (RA)-regulated promoters, protection of CpG islands from hypermethylation, and active demethylation of tissue-specific developmentally and hormonally regulated promoters and enhancers. TDG interacts with the deaminase AID and the damage response protein GADD45a. These findings highlight a dual role for TDG in promoting proper epigenetic states during development and suggest a two-step mechanism for DNA demethylation in mammals, whereby 5-methylcytosine and 5-hydroxymethylcytosine are first deaminated by AID to thymine and 5-hydroxymethyluracil, respectively, followed by TDG-mediated thymine and 5-hydroxymethyluracil excision repair. PaperClip:

KW - 5-Methylcytosine/metabolism

KW - Animals

KW - Cell Cycle Proteins/metabolism

KW - Cytidine Deaminase/metabolism

KW - Cytosine/analogs & derivatives

KW - DNA Methylation

KW - Embryonic Development

KW - Female

KW - Gene Expression Regulation, Developmental

KW - Gene Knock-In Techniques

KW - Male

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Nuclear Proteins/metabolism

KW - Promoter Regions, Genetic

KW - Thymine DNA Glycosylase/genetics

KW - Transcription, Genetic

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U2 - 10.1016/j.cell.2011.06.020

DO - 10.1016/j.cell.2011.06.020

M3 - Article

C2 - 21722948

SN - 0092-8674

VL - 146

SP - 67

EP - 79

JO - Cell

JF - Cell

IS - 1

ER -

Thymine DNA glycosylase is essential for active DNA demethylation by linked deamination-base excision repair

Abstract

Keywords

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