schliessen

Filtern

 

Bibliotheken

Human telomerase model shows the role of the TEN domain in advancing the double helix for the next polymerization step

Telomerases constitute a group of specialized ribonucleoprotein enzymes that remediate chromosomal shrinkage resulting from the “end-replication” problem. Defects in telomere length regulation are associated with several diseases as well as with aging and cancer. Despite significant progress in unde... Full description

Journal Title: Proceedings of the National Academy of Sciences 07 June 2011, Vol.108(23), p.9443
Main Author: Kamil Steczkiewicz
Other Authors: Michael T. Zimmermann , Mateusz Kurcinski , Benjamin A. Lewis , Drena Dobbs , Andrzej Kloczkowski , Robert L. Jernigan , Andrzej Kolinski , Krzysztof Ginalski
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: ISSN: 0027-8424 ; E-ISSN: 1091-6490 ; DOI: 10.1073/pnas.1015399108
Zum Text:
SendSend as email Add to Book BagAdd to Book Bag
Staff View
recordid: pnas_s108_23_9443
title: Human telomerase model shows the role of the TEN domain in advancing the double helix for the next polymerization step
format: Article
creator:
  • Kamil Steczkiewicz
  • Michael T. Zimmermann
  • Mateusz Kurcinski
  • Benjamin A. Lewis
  • Drena Dobbs
  • Andrzej Kloczkowski
  • Robert L. Jernigan
  • Andrzej Kolinski
  • Krzysztof Ginalski
subjects:
  • Sciences (General)
ispartof: Proceedings of the National Academy of Sciences, 07 June 2011, Vol.108(23), p.9443
description: Telomerases constitute a group of specialized ribonucleoprotein enzymes that remediate chromosomal shrinkage resulting from the “end-replication” problem. Defects in telomere length regulation are associated with several diseases as well as with aging and cancer. Despite significant progress in understanding the roles of telomerase, the complete structure of the human telomerase enzyme bound to telomeric DNA remains elusive, with the detailed molecular mechanism of telomere elongation still unknown. By application of computational methods for distant homology detection, comparative modeling, and molecular docking, guided by available experimental data, we have generated a three-dimensional structural model of a partial telomerase elongation complex composed of three essential protein domains bound to a single-stranded telomeric DNA sequence in the form of a heteroduplex with the template region of the human RNA subunit, TER. This model provides a structural mechanism for the processivity of telomerase and offers new insights into elongation. We conclude that the RNA∶DNA heteroduplex is constrained by the telomerase TEN domain through repeated extension cycles and that the TEN domain controls the process by moving the template ahead one base at a time by translation and rotation of the double helix. The RNA region directly following the template can bind complementarily to the newly synthesized telomeric DNA, while the template itself is reused in the telomerase active site during the next reaction cycle. This first structural model of the human telomerase enzyme provides many details of the molecular mechanism of telomerase and immediately provides an important target for rational drug design.
language: eng
source:
identifier: ISSN: 0027-8424 ; E-ISSN: 1091-6490 ; DOI: 10.1073/pnas.1015399108
fulltext: fulltext_linktorsrc
issn:
  • 0027-8424
  • 00278424
  • 1091-6490
  • 10916490
url: Link


@attributes
ID915844197
RANK0.07
NO1
SEARCH_ENGINEprimo_central_multiple_fe
SEARCH_ENGINE_TYPEPrimo Central Search Engine
LOCALfalse
PrimoNMBib
record
control
sourcerecordid108_23_9443
sourceidpnas_s
recordidTN_pnas_s108_23_9443
sourcesystemOther
dbid
0PNE
1RNA
pqid871385605
galeid259679198
display
typearticle
titleHuman telomerase model shows the role of the TEN domain in advancing the double helix for the next polymerization step
creatorKamil Steczkiewicz ; Michael T. Zimmermann ; Mateusz Kurcinski ; Benjamin A. Lewis ; Drena Dobbs ; Andrzej Kloczkowski ; Robert L. Jernigan ; Andrzej Kolinski ; Krzysztof Ginalski
ispartofProceedings of the National Academy of Sciences, 07 June 2011, Vol.108(23), p.9443
identifier
subjectSciences (General)
descriptionTelomerases constitute a group of specialized ribonucleoprotein enzymes that remediate chromosomal shrinkage resulting from the “end-replication” problem. Defects in telomere length regulation are associated with several diseases as well as with aging and cancer. Despite significant progress in understanding the roles of telomerase, the complete structure of the human telomerase enzyme bound to telomeric DNA remains elusive, with the detailed molecular mechanism of telomere elongation still unknown. By application of computational methods for distant homology detection, comparative modeling, and molecular docking, guided by available experimental data, we have generated a three-dimensional structural model of a partial telomerase elongation complex composed of three essential protein domains bound to a single-stranded telomeric DNA sequence in the form of a heteroduplex with the template region of the human RNA subunit, TER. This model provides a structural mechanism for the processivity of telomerase and offers new insights into elongation. We conclude that the RNA∶DNA heteroduplex is constrained by the telomerase TEN domain through repeated extension cycles and that the TEN domain controls the process by moving the template ahead one base at a time by translation and rotation of the double helix. The RNA region directly following the template can bind complementarily to the newly synthesized telomeric DNA, while the template itself is reused in the telomerase active site during the next reaction cycle. This first structural model of the human telomerase enzyme provides many details of the molecular mechanism of telomerase and immediately provides an important target for rational drug design.
languageeng
source
version9
lds50peer_reviewed
links
openurl$$Topenurl_article
openurlfulltext$$Topenurlfull_article
linktorsrc$$Uhttp://www.pnas.org/content/108/23/9443.abstract$$EView_full_text_in_National_Academy_of_Sciences_(Access_to_full_text_may_be_restricted)
search
creatorcontrib
0Kamil Steczkiewicz
1Michael T. Zimmermann
2Mateusz Kurcinski
3Benjamin A. Lewis
4Drena Dobbs
5Andrzej Kloczkowski
6Robert L. Jernigan
7Andrzej Kolinski
8Krzysztof Ginalski
titleHuman telomerase model shows the role of the TEN domain in advancing the double helix for the next polymerization step
description

Telomerases constitute a group of specialized ribonucleoprotein enzymes that remediate chromosomal shrinkage resulting from the “end-replication” problem. Defects in telomere length regulation are associated with several diseases as well as with aging and cancer. Despite significant progress in understanding the roles of telomerase, the complete structure of the human telomerase enzyme bound to telomeric DNA remains elusive, with the detailed molecular mechanism of telomere elongation still unknown. By application of computational methods for distant homology detection, comparative modeling, and molecular docking, guided by available experimental data, we have generated a three-dimensional structural model of a partial telomerase elongation complex composed of three essential protein domains bound to a single-stranded telomeric DNA sequence in the form of a heteroduplex with the template region of the human RNA subunit, TER. This model provides a structural mechanism for the processivity of telomerase and offers new insights into elongation. We conclude that the RNA∶DNA heteroduplex is constrained by the telomerase TEN domain through repeated extension cycles and that the TEN domain controls the process by moving the template ahead one base at a time by translation and rotation of the double helix. The RNA region directly following the template can bind complementarily to the newly synthesized telomeric DNA, while the template itself is reused in the telomerase active site during the next reaction cycle. This first structural model of the human telomerase enzyme provides many details of the molecular mechanism of telomerase and immediately provides an important target for rational drug design.

subjectSciences (General)
general
0English
1National Acad Sciences
210.1073/pnas.1015399108
3PNAS (National Academy of Sciences)
4National Academy of Sciences (U.S.)
sourceidpnas_s
recordidpnas_s108_23_9443
issn
00027-8424
100278424
21091-6490
310916490
rsrctypearticle
creationdate2011
addtitleProceedings of the National Academy of Sciences
searchscope
0pnas_full
1pnas4
2pnas5
scope
0pnas_full
1pnas4
2pnas5
lsr45$$EView_full_text_in_National_Academy_of_Sciences_(Access_to_full_text_may_be_restricted)
tmp01
0PNAS (National Academy of Sciences)
1National Academy of Sciences (U.S.)
tmp02
0PNE
1RNA
startdate20110607
enddate20110607
lsr40Proceedings of the National Academy of Sciences, 07 June 2011, Vol.108 (23), p.9443
doi10.1073/pnas.1015399108
citationpf 9443 vol 108 issue 23
lsr30VSR-Enriched:[pages, galeid, pqid]
sort
titleHuman telomerase model shows the role of the TEN domain in advancing the double helix for the next polymerization step
authorKamil Steczkiewicz ; Michael T. Zimmermann ; Mateusz Kurcinski ; Benjamin A. Lewis ; Drena Dobbs ; Andrzej Kloczkowski ; Robert L. Jernigan ; Andrzej Kolinski ; Krzysztof Ginalski
creationdate20110607
lso0120110607
facets
frbrgroupid5883566508454917632
frbrtype5
newrecords20190724
languageeng
topicSciences (General)
collection
0PNAS (National Academy of Sciences)
1National Academy of Sciences (U.S.)
prefilterarticles
rsrctypearticles
creatorcontrib
0Kamil Steczkiewicz
1Michael T. Zimmermann
2Mateusz Kurcinski
3Benjamin A. Lewis
4Drena Dobbs
5Andrzej Kloczkowski
6Robert L. Jernigan
7Andrzej Kolinski
8Krzysztof Ginalski
jtitleProceedings of the National Academy of Sciences
creationdate2011
toplevelpeer_reviewed
delivery
delcategoryRemote Search Resource
fulltextfulltext_linktorsrc
addata
au
0Kamil Steczkiewicz
1Michael T. Zimmermann
2Mateusz Kurcinski
3Benjamin A. Lewis
4Drena Dobbs
5Andrzej Kloczkowski
6Robert L. Jernigan
7Andrzej Kolinski
8Krzysztof Ginalski
atitleHuman telomerase model shows the role of the TEN domain in advancing the double helix for the next polymerization step
jtitleProceedings of the National Academy of Sciences
risdate20110607
volume108
issue23
spage9443
issn0027-8424
eissn1091-6490
formatjournal
genrearticle
ristypeJOUR
abstract

Telomerases constitute a group of specialized ribonucleoprotein enzymes that remediate chromosomal shrinkage resulting from the “end-replication” problem. Defects in telomere length regulation are associated with several diseases as well as with aging and cancer. Despite significant progress in understanding the roles of telomerase, the complete structure of the human telomerase enzyme bound to telomeric DNA remains elusive, with the detailed molecular mechanism of telomere elongation still unknown. By application of computational methods for distant homology detection, comparative modeling, and molecular docking, guided by available experimental data, we have generated a three-dimensional structural model of a partial telomerase elongation complex composed of three essential protein domains bound to a single-stranded telomeric DNA sequence in the form of a heteroduplex with the template region of the human RNA subunit, TER. This model provides a structural mechanism for the processivity of telomerase and offers new insights into elongation. We conclude that the RNA∶DNA heteroduplex is constrained by the telomerase TEN domain through repeated extension cycles and that the TEN domain controls the process by moving the template ahead one base at a time by translation and rotation of the double helix. The RNA region directly following the template can bind complementarily to the newly synthesized telomeric DNA, while the template itself is reused in the telomerase active site during the next reaction cycle. This first structural model of the human telomerase enzyme provides many details of the molecular mechanism of telomerase and immediately provides an important target for rational drug design.

pubNational Acad Sciences
doi10.1073/pnas.1015399108
urlhttp://www.pnas.org/content/108/23/9443.abstract
lad01Proceedings of the National Academy of Sciences
pages9443-9448
date2011-06-07