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Cited by 163Genomics and Chromatin DynamicsEpigenetics and DNA MethylationCancer-related gene regulation

The DOI matches its Crossref record; 35 of the 35 references it cites were found in a registry or an index.

N ε -Formylation of lysine is a widespread post-translational modification of nuclear proteins occurring at residues involved in regulation of chromatin function

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Wiśniewski, Jacek R., Zougman, Alexandre, Mann, Matthias·2008·Nucleic Acids Research
DOI 10.1093/nar/gkm1057PMC PMC2241850
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Abstract

Post-translational modification of histones and other chromosomal proteins regulates chromatin conformation and gene activity. Methylation and acetylation of lysyl residues are among the most frequently described modifications in these proteins. Whereas these modifications have been studied in detail, very little is known about a recently discovered chemical modification, the N(epsilon)-lysine formylation, in histones and other nuclear proteins. Here we mapped, for the first time, the sites of lysine formylation in histones and several other nuclear proteins. We found that core and linker histones are formylated at multiple lysyl residues located both in the tails and globular domains of histones. In core histones, formylation was found at lysyl residues known to be involved in organization of nucleosomal particles that are frequently acetylated and methylated. In linker histones and high mobility group proteins, multiple formylation sites were mapped to residues with important role in DNA binding. N(epsilon)-lysine formylation in chromosomal proteins is relatively abundant, suggesting that it may interfere with epigenetic mechanisms governing chromatin function, which could lead to deregulation of the cell and disease.

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Crossref · 10.1093/nar/gkm1057

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Figure 1. (A) Acetylated, dimethylated and formylated lysyl residues show similar structures. (B) Complete mass separation of the otherwise identical dimethylated and formylated peptides. Boxplot of mass deviations from theoretical masses for formylation and dimethylation in histone H3 measured using the LTQ-Orbitrap instrument. The box represents the interquartile range of 25–75%, the center line represents median, and ‘whiskers’ (small horizontal lines) extend to the most extreme ratio up to 1.5-fold interquartile range. The mass differences of dimethylated or formylated peptides are 28.0313 and 27.9949 Da, respectively, versus unmodified peptide. Mass deviations for dimethylation are taken from Supplementary Table S2.
Figure 1. (A) Acetylated, dimethylated and formylated lysyl residues show similar structures. (B) Complete mass separation of the otherwise identical dimethylated and formylated peptides. Boxplot of mass deviations from theoretical masses for formylation and dimethylation in histone H3 measured using the LTQ-Orbitrap instrument. The box represents the interquartile range of 25–75%, the center line represents median, and ‘whiskers’ (small horizontal lines) extend to the most extreme ratio up to 1.5-fold interquartile range. The mass differences of dimethylated or formylated peptides are 28.0313 and 27.9949 Da, respectively, versus unmodified peptide. Mass deviations for dimethylation are taken from Supplementary Table S2.CC BY-NC · PubMed Central
Figure 2. The MS/MS fragmentation spectra of (A) EIAQDFfKTDLR formylated and (B) EIAQDFdmKTDLR dimethylated peptides of Histone H3. The major groups of ions produced on cleavage of peptide bonds by low energy collision fragmentation are b ions extending from the N-terminus of a peptide, and y ions extending from its C-terminal part. The comprehensive introduction to the peptide sequencing by mass spectrometry is given by Steen and Mann (33).
Figure 2. The MS/MS fragmentation spectra of (A) EIAQDFfKTDLR formylated and (B) EIAQDFdmKTDLR dimethylated peptides of Histone H3. The major groups of ions produced on cleavage of peptide bonds by low energy collision fragmentation are b ions extending from the N-terminus of a peptide, and y ions extending from its C-terminal part. The comprehensive introduction to the peptide sequencing by mass spectrometry is given by Steen and Mann (33).CC BY-NC · PubMed Central
Figure 3. High accuracy MS/MS spectra of peptides dimethylated (A, C, E) and formylated (B, D, F) at the same residue, respectively. (A and B) Modifications at K-108 in histone H2B. (C and D) Modifications at K-43 in histone H2B. (E and F) Modifications at K-77 in histone H4. In contrast to dimethylation, formylation was observed mainly on peptides that were not cut at the modified lysyl residue. An example of the MS and MS/MS data interpretation: after the MS scan, the ESYSVYVYKVLK peptide (B) was identified as carrying an extra mass of 27.995 Da that corresponds to the delta mass of formylation. Peptide fragmentation analysis reveals that, starting from y4 ion (KVLK), the formyl group is added to y-ion series. The observations, additionally supported by the presence of b10 (ESYSVYVYKV) and b11 (ESYSVYVYKVL) ions with the mass shift indicative of formylation, unambiguously position the modification at the middle lysyl residue—ESYSVYVYfKVLK. Average absolute mass accuracy of all assigned peaks was better than 2 p.p.m.
Figure 3. High accuracy MS/MS spectra of peptides dimethylated (A, C, E) and formylated (B, D, F) at the same residue, respectively. (A and B) Modifications at K-108 in histone H2B. (C and D) Modifications at K-43 in histone H2B. (E and F) Modifications at K-77 in histone H4. In contrast to dimethylation, formylation was observed mainly on peptides that were not cut at the modified lysyl residue. An example of the MS and MS/MS data interpretation: after the MS scan, the ESYSVYVYKVLK peptide (B) was identified as carrying an extra mass of 27.995 Da that corresponds to the delta mass of formylation. Peptide fragmentation analysis reveals that, starting from y4 ion (KVLK), the formyl group is added to y-ion series. The observations, additionally supported by the presence of b10 (ESYSVYVYKV) and b11 (ESYSVYVYKVL) ions with the mass shift indicative of formylation, unambiguously position the modification at the middle lysyl residue—ESYSVYVYfKVLK. Average absolute mass accuracy of all assigned peaks was better than 2 p.p.m.CC BY-NC · PubMed Central
Figure 4. Dimethylated (dm) and formylated (f) forms of the peptide LLLPGELA*K (from histone H2B; K-108) resolved by chromatography. Inserts show the mass envelopes of dimethylated and formylated peptides.
Figure 4. Dimethylated (dm) and formylated (f) forms of the peptide LLLPGELA*K (from histone H2B; K-108) resolved by chromatography. Inserts show the mass envelopes of dimethylated and formylated peptides.CC BY-NC · PubMed Central

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Metadata

Authors
Wiśniewski, J. R., Zougman, A., & Mann, M.
Affiliations
Max Planck Society (DE)
Corresponding author
Wiśniewski, Jacek R.
ORCID
Venue
Nucleic Acids Research
Publisher
Oxford University Press (OUP)
Published
2007-12-01
Volume
36
Issue
2
Pages
570-577
ISSN
  • 0305-1048 (ISSN-L)
  • 1362-4962
DOI
10.1093/nar/gkm1057
PMC
PMC2241850
OpenAlex
W2044731117
Cited by
163
References
35
Citations by year
2026: 6 · 2025: 5 · 2024: 6 · 2023: 5 · 2022: 8 · 2021: 9 · 2020: 14 · 2019: 9 · 2018: 8 · 2017: 13 · 2016: 13 · 2015: 13 · 2014: 14 · 2013: 12 · 2012: 7
FWCI
1.99
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • Nucleic Acids Research (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • Max Planck Institute for Plasma Physics (submittedVersion)
  • MPG.PuRe (Max Planck Society) (submittedVersion)
Funders
  • European Commission
  • Uniwersytet Medyczny im. Piastów Slaskich we Wroclawiu
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer-related gene regulation
Keywords
post-translational modification, histones, core histones, linker histones, high mobility group proteins, chromatin regulation, epigenetic regulation, nucleosome, DNA binding, nuclear proteins
MeSH terms
Aldehydes, Animals, Chromatin, Chromosomal Proteins, Non-Histone, High Mobility Group Proteins, Histones, Humans, Lysine, Mice, Inbred C57BL, Nuclear Proteins, Protein Processing, Post-Translational, Cell Line, Tumor, Mice, Tandem Mass Spectrometry

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