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Cell Cycle Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/kccy20
DNMT1-associated DNA methylation changes in cancer a
a
Pavel Bashtrykov & Albert Jeltsch a
Institute of Biochemistry, Stuttgart University, Stuttgart, Germany Accepted author version posted online: 21 Nov 2014.
Click for updates To cite this article: Pavel Bashtrykov & Albert Jeltsch (2014): DNMT1-associated DNA methylation changes in cancer, Cell Cycle, DOI: 10.4161/15384101.2014.989963 To link to this article: http://dx.doi.org/10.4161/15384101.2014.989963
Disclaimer: This is a version of an unedited manuscript that has been accepted for publication. As a service to authors and researchers we are providing this version of the accepted manuscript (AM). Copyediting, typesetting, and review of the resulting proof will be undertaken on this manuscript before final publication of the Version of Record (VoR). During production and pre-press, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal relate to this version also.
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http:// www.tandfonline.com/page/terms-and-conditions
DNMT1-associated DNA methylation changes in cancer Comment on: WuB-K, et al. Cell Cycle 2014; 13(20) Pavel Bashtrykov and Albert Jeltsch* Institute of Biochemistry, Stuttgart University, Stuttgart, Germany
ip t
*Corresponding author: Albert Jeltsch, [email protected]
Cancer arises as a consequence of somatic mutations and clonal amplification of tumor cells.
cr
However, it has been known since many years that cancer cells also accumulate a multitude of
us
DNA methylation changes were observed in many tumors. On one hand promoters of tumor suppressor genes often are hypermethylated leading to the silencing of the genes. On the other hand a global DNA hypomethylation including heterochromatic repetitive elements is observed which leads
an
to genomic instability. In a publication in this issue of Cell Cycle, Wu et al. for the first time present a mechanism that could explain both of these inverse changes by a mutation in DNMT1, an important
M
DNA methyltransferase in human cells.2
In mammals, DNA methylation mainly takes place at CpG sites, where methylation occurs on both
ed
DNA strands and it cycles between full methylation and hemimethylation after DNA replication. DNMT1 has a preferences for the methylation of hemimethylated CpG sites and it was initially believed to purely function as maintenance methyltransferase, which copies DNA methylation patterns
pt
after replication. However, it became clear that DNA methylation is dynamically regulated and the control of Dnmts including DNMT1 plays a central role in the generation and maintenance of DNA
ce
methylation patterns.3
DNMT1 is a large multidomain protein. Its C-terminal catalytic domain is under tight allosteric control by several N-terminal domains, including the RFTS domain (RFTD), which has three roles in
Ac
Downloaded by [Erciyes University] at 03:15 13 January 2015
epigenetic alterations including aberrant DNA methylation.1 Interestingly, two converse trends of
the regulation of DNMT1:2, 4-7 First, it blocks the catalytic pocket and by this it reduces the catalytic activity of DNMT1. Second, it interacts with other proteins including UHRF1, which can target DNMT1 to replication foci (via its interaction with hemimethylated DNA), but also to heterochromatin (via its interaction with H3K9 methylated histones). Third, interaction with UHRF1 can relieve the RFTD mediated allosteric repression of DNMT1 activity. Wu et al. now show that deletion of the RFTS domain leads to converse changes of DNA methylation which mimic the alterations observed in cancer cells (Fig. 1). One the one hand, the activity of DNMT1 is increased leading to DNA hypermethylation at sites, where DNMT1 is targeted in an RFTD independent manner, for example at promoter region of tumor suppressor genes. One the other hand, deletion of 1
RFTD disrupts the interaction of DNMT1 and UHRF1 leading to the loss of heterochromatic localization DNMT1 and hypomethylation of heterochromatic SAT2 elements. It is conceivable to speculate that somatic DNMT1 mutations in cancer cells which disrupt folding of the RFTS domain could have similar effects. Therefore, the paper by Wu et al. is an important contribution to our
ip t
understanding of the causes of the complex DNA methylation changes observed in cancer cells.
Baylin, S. B. & Jones, P.A. Nat. Rev. Cancer 2011; Vol. 11(10), 726-734
2.
Wu B.-K. et al. Cell Cycle 2014; Vol. 13(20)
3.
Jeltsch A. & Jurkowska R. Z. TIBS 2014; Vol. 39(7), 310-318
4.
Syeda, F. J. Biol. Chem. 2011; Vol. 286(17), 15344-15351
5.
Bashtrykov, P. et al. J. Biol. Chem. 2014; Vol. 289(7), 4106-4115
6.
Bashtrykov, P. et al. ChemBioChem 2014; Vol. 15(5), 743-748
7.
Berkyurek, A. C. J. Biol. Chem. 2014; Vol. 289(1), 379-386
ce
pt
ed
M
an
us
cr
1.
Ac
Downloaded by [Erciyes University] at 03:15 13 January 2015
References
2
cr us
an
Fig. 1: Schematic picture of the changes in DNA methylation caused by the loss-of-function of the RFTS domain (RFTD) in DNMT1. Wildtype DNMT1 is recruited by the interaction of UHRF1 with RFTD to heterochromatin. At the same time, the interaction of UHRF1 with RFTD relieves the
M
inhibition of DNMT1 caused by binding of RFTD to the catalytic pocket leading to strong methylation of heterochromatic repeats. In the DNMT1 mutant which lost the RFTD this targeting does not occur and the methylation of the heterochromatic DNA is reduced. At the same time DNMT1 is recruited by
ed
other factors to euchromatic elements like promoters in an RFTD independent fashion. Here, the activity of wildtype DNMT1 is inhibited by the RFTD and the DNMT1 mutant without RFTD is more
ce
pt
active, leading to higher methylation of promoter regions.
Ac
Downloaded by [Erciyes University] at 03:15 13 January 2015
ip t
Figure and figure legend
3
Cell Cycle Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/kccy20
DNMT1-associated DNA methylation changes in cancer a
a
Pavel Bashtrykov & Albert Jeltsch a
Institute of Biochemistry, Stuttgart University, Stuttgart, Germany Accepted author version posted online: 21 Nov 2014.
Click for updates To cite this article: Pavel Bashtrykov & Albert Jeltsch (2014): DNMT1-associated DNA methylation changes in cancer, Cell Cycle, DOI: 10.4161/15384101.2014.989963 To link to this article: http://dx.doi.org/10.4161/15384101.2014.989963
Disclaimer: This is a version of an unedited manuscript that has been accepted for publication. As a service to authors and researchers we are providing this version of the accepted manuscript (AM). Copyediting, typesetting, and review of the resulting proof will be undertaken on this manuscript before final publication of the Version of Record (VoR). During production and pre-press, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal relate to this version also.
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http:// www.tandfonline.com/page/terms-and-conditions
DNMT1-associated DNA methylation changes in cancer Comment on: WuB-K, et al. Cell Cycle 2014; 13(20) Pavel Bashtrykov and Albert Jeltsch* Institute of Biochemistry, Stuttgart University, Stuttgart, Germany
ip t
*Corresponding author: Albert Jeltsch, [email protected]
Cancer arises as a consequence of somatic mutations and clonal amplification of tumor cells.
cr
However, it has been known since many years that cancer cells also accumulate a multitude of
us
DNA methylation changes were observed in many tumors. On one hand promoters of tumor suppressor genes often are hypermethylated leading to the silencing of the genes. On the other hand a global DNA hypomethylation including heterochromatic repetitive elements is observed which leads
an
to genomic instability. In a publication in this issue of Cell Cycle, Wu et al. for the first time present a mechanism that could explain both of these inverse changes by a mutation in DNMT1, an important
M
DNA methyltransferase in human cells.2
In mammals, DNA methylation mainly takes place at CpG sites, where methylation occurs on both
ed
DNA strands and it cycles between full methylation and hemimethylation after DNA replication. DNMT1 has a preferences for the methylation of hemimethylated CpG sites and it was initially believed to purely function as maintenance methyltransferase, which copies DNA methylation patterns
pt
after replication. However, it became clear that DNA methylation is dynamically regulated and the control of Dnmts including DNMT1 plays a central role in the generation and maintenance of DNA
ce
methylation patterns.3
DNMT1 is a large multidomain protein. Its C-terminal catalytic domain is under tight allosteric control by several N-terminal domains, including the RFTS domain (RFTD), which has three roles in
Ac
Downloaded by [Erciyes University] at 03:15 13 January 2015
epigenetic alterations including aberrant DNA methylation.1 Interestingly, two converse trends of
the regulation of DNMT1:2, 4-7 First, it blocks the catalytic pocket and by this it reduces the catalytic activity of DNMT1. Second, it interacts with other proteins including UHRF1, which can target DNMT1 to replication foci (via its interaction with hemimethylated DNA), but also to heterochromatin (via its interaction with H3K9 methylated histones). Third, interaction with UHRF1 can relieve the RFTD mediated allosteric repression of DNMT1 activity. Wu et al. now show that deletion of the RFTS domain leads to converse changes of DNA methylation which mimic the alterations observed in cancer cells (Fig. 1). One the one hand, the activity of DNMT1 is increased leading to DNA hypermethylation at sites, where DNMT1 is targeted in an RFTD independent manner, for example at promoter region of tumor suppressor genes. One the other hand, deletion of 1
RFTD disrupts the interaction of DNMT1 and UHRF1 leading to the loss of heterochromatic localization DNMT1 and hypomethylation of heterochromatic SAT2 elements. It is conceivable to speculate that somatic DNMT1 mutations in cancer cells which disrupt folding of the RFTS domain could have similar effects. Therefore, the paper by Wu et al. is an important contribution to our
ip t
understanding of the causes of the complex DNA methylation changes observed in cancer cells.
Baylin, S. B. & Jones, P.A. Nat. Rev. Cancer 2011; Vol. 11(10), 726-734
2.
Wu B.-K. et al. Cell Cycle 2014; Vol. 13(20)
3.
Jeltsch A. & Jurkowska R. Z. TIBS 2014; Vol. 39(7), 310-318
4.
Syeda, F. J. Biol. Chem. 2011; Vol. 286(17), 15344-15351
5.
Bashtrykov, P. et al. J. Biol. Chem. 2014; Vol. 289(7), 4106-4115
6.
Bashtrykov, P. et al. ChemBioChem 2014; Vol. 15(5), 743-748
7.
Berkyurek, A. C. J. Biol. Chem. 2014; Vol. 289(1), 379-386
ce
pt
ed
M
an
us
cr
1.
Ac
Downloaded by [Erciyes University] at 03:15 13 January 2015
References
2
cr us
an
Fig. 1: Schematic picture of the changes in DNA methylation caused by the loss-of-function of the RFTS domain (RFTD) in DNMT1. Wildtype DNMT1 is recruited by the interaction of UHRF1 with RFTD to heterochromatin. At the same time, the interaction of UHRF1 with RFTD relieves the
M
inhibition of DNMT1 caused by binding of RFTD to the catalytic pocket leading to strong methylation of heterochromatic repeats. In the DNMT1 mutant which lost the RFTD this targeting does not occur and the methylation of the heterochromatic DNA is reduced. At the same time DNMT1 is recruited by
ed
other factors to euchromatic elements like promoters in an RFTD independent fashion. Here, the activity of wildtype DNMT1 is inhibited by the RFTD and the DNMT1 mutant without RFTD is more
ce
pt
active, leading to higher methylation of promoter regions.
Ac
Downloaded by [Erciyes University] at 03:15 13 January 2015
ip t
Figure and figure legend
3
