Catalytic and non-catalytic mechanisms of histone H4 lysine 20 methyltransferase SUV420H1
Copyright © 2023 Elsevier Inc. All rights reserved..
SUV420H1 di- and tri-methylates histone H4 lysine 20 (H4K20me2/H4K20me3) and plays crucial roles in DNA replication, repair, and heterochromatin formation. It is dysregulated in several cancers. Many of these processes were linked to its catalytic activity. However, deletion and inhibition of SUV420H1 have shown distinct phenotypes, suggesting that the enzyme likely has uncharacterized non-catalytic activities. Our cryoelectron microscopy (cryo-EM), biochemical, biophysical, and cellular analyses reveal how SUV420H1 recognizes its nucleosome substrates, and how histone variant H2A.Z stimulates its catalytic activity. SUV420H1 binding to nucleosomes causes a dramatic detachment of nucleosomal DNA from the histone octamer, which is a non-catalytic activity. We hypothesize that this regulates the accessibility of large macromolecular complexes to chromatin. We show that SUV420H1 can promote chromatin condensation, another non-catalytic activity that we speculate is needed for its heterochromatin functions. Together, our studies uncover and characterize the catalytic and non-catalytic mechanisms of SUV420H1, a key histone methyltransferase that plays an essential role in genomic stability.
| Errataetall: | |
|---|---|
| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2023 |
|---|---|
| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:83 |
|---|---|
| Enthalten in: |
Molecular cell - 83(2023), 16 vom: 17. Aug., Seite 2872-2883.e7 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Abini-Agbomson, Stephen [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 25.08.2023 Date Revised 06.09.2023 published: Print UpdateOf: bioRxiv. 2023 Mar 19;:. - PMID 36993485 Citation Status MEDLINE |
|---|
| doi: |
10.1016/j.molcel.2023.07.020 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM360943497 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM360943497 | ||
| 003 | DE-627 | ||
| 005 | 20231226084111.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.molcel.2023.07.020 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1203.xml |
| 035 | |a (DE-627)NLM360943497 | ||
| 035 | |a (NLM)37595555 | ||
| 035 | |a (PII)S1097-2765(23)00564-6 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Abini-Agbomson, Stephen |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Catalytic and non-catalytic mechanisms of histone H4 lysine 20 methyltransferase SUV420H1 |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 25.08.2023 | ||
| 500 | |a Date Revised 06.09.2023 | ||
| 500 | |a published: Print | ||
| 500 | |a UpdateOf: bioRxiv. 2023 Mar 19;:. - PMID 36993485 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023 Elsevier Inc. All rights reserved. | ||
| 520 | |a SUV420H1 di- and tri-methylates histone H4 lysine 20 (H4K20me2/H4K20me3) and plays crucial roles in DNA replication, repair, and heterochromatin formation. It is dysregulated in several cancers. Many of these processes were linked to its catalytic activity. However, deletion and inhibition of SUV420H1 have shown distinct phenotypes, suggesting that the enzyme likely has uncharacterized non-catalytic activities. Our cryoelectron microscopy (cryo-EM), biochemical, biophysical, and cellular analyses reveal how SUV420H1 recognizes its nucleosome substrates, and how histone variant H2A.Z stimulates its catalytic activity. SUV420H1 binding to nucleosomes causes a dramatic detachment of nucleosomal DNA from the histone octamer, which is a non-catalytic activity. We hypothesize that this regulates the accessibility of large macromolecular complexes to chromatin. We show that SUV420H1 can promote chromatin condensation, another non-catalytic activity that we speculate is needed for its heterochromatin functions. Together, our studies uncover and characterize the catalytic and non-catalytic mechanisms of SUV420H1, a key histone methyltransferase that plays an essential role in genomic stability | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, U.S. Gov't, Non-P.H.S. | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a DNA repair | |
| 650 | 4 | |a H4K20 methylation | |
| 650 | 4 | |a SUV420H1 | |
| 650 | 4 | |a chromatin | |
| 650 | 4 | |a chromatin condensation | |
| 650 | 4 | |a chromatin epigenetics | |
| 650 | 4 | |a heterochromatin | |
| 650 | 4 | |a histone lysine methyltransferase | |
| 650 | 4 | |a histone variant H2A.Z | |
| 650 | 4 | |a nucleosomes | |
| 650 | 7 | |a Chromatin |2 NLM | |
| 650 | 7 | |a Heterochromatin |2 NLM | |
| 650 | 7 | |a Histone-Lysine N-Methyltransferase |2 NLM | |
| 650 | 7 | |a EC 2.1.1.43 |2 NLM | |
| 650 | 7 | |a Histones |2 NLM | |
| 650 | 7 | |a Lysine |2 NLM | |
| 650 | 7 | |a K3Z4F929H6 |2 NLM | |
| 650 | 7 | |a Nucleosomes |2 NLM | |
| 650 | 7 | |a KMT5C protein, human |2 NLM | |
| 650 | 7 | |a EC 2.1.1.43 |2 NLM | |
| 700 | 1 | |a Gretarsson, Kristjan |e verfasserin |4 aut | |
| 700 | 1 | |a Shih, Rochelle M |e verfasserin |4 aut | |
| 700 | 1 | |a Hsieh, Laura |e verfasserin |4 aut | |
| 700 | 1 | |a Lou, Tracy |e verfasserin |4 aut | |
| 700 | 1 | |a De Ioannes, Pablo |e verfasserin |4 aut | |
| 700 | 1 | |a Vasilyev, Nikita |e verfasserin |4 aut | |
| 700 | 1 | |a Lee, Rachel |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Miao |e verfasserin |4 aut | |
| 700 | 1 | |a Simon, Matthew D |e verfasserin |4 aut | |
| 700 | 1 | |a Armache, Jean-Paul |e verfasserin |4 aut | |
| 700 | 1 | |a Nudler, Evgeny |e verfasserin |4 aut | |
| 700 | 1 | |a Narlikar, Geeta |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Shixin |e verfasserin |4 aut | |
| 700 | 1 | |a Lu, Chao |e verfasserin |4 aut | |
| 700 | 1 | |a Armache, Karim-Jean |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Molecular cell |d 1998 |g 83(2023), 16 vom: 17. Aug., Seite 2872-2883.e7 |w (DE-627)NLM095914765 |x 1097-4164 |7 nnns |
| 773 | 1 | 8 | |g volume:83 |g year:2023 |g number:16 |g day:17 |g month:08 |g pages:2872-2883.e7 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.molcel.2023.07.020 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 83 |j 2023 |e 16 |b 17 |c 08 |h 2872-2883.e7 | ||