Cargando…

Mre11 exonuclease activity removes the chain-terminating nucleoside analog gemcitabine from the nascent strand during DNA replication

The Mre11 nuclease is involved in early responses to DNA damage, often mediated by its role in DNA end processing. MRE11 mutations and aberrant expression are associated with carcinogenesis and cancer treatment outcomes. While, in recent years, progress has been made in understanding the role of Mre...

Descripción completa

Detalles Bibliográficos
Autores principales: Boeckemeier, L., Kraehenbuehl, R., Keszthelyi, A., Gasasira, M. U., Vernon, E. G., Beardmore, R., Vågbø, C. B., Chaplin, D., Gollins, S., Krokan, H. E., Lambert, S. A. E., Paizs, B., Hartsuiker, E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7259961/
https://www.ncbi.nlm.nih.gov/pubmed/32523988
http://dx.doi.org/10.1126/sciadv.aaz4126
_version_ 1783540237197115392
author Boeckemeier, L.
Kraehenbuehl, R.
Keszthelyi, A.
Gasasira, M. U.
Vernon, E. G.
Beardmore, R.
Vågbø, C. B.
Chaplin, D.
Gollins, S.
Krokan, H. E.
Lambert, S. A. E.
Paizs, B.
Hartsuiker, E.
author_facet Boeckemeier, L.
Kraehenbuehl, R.
Keszthelyi, A.
Gasasira, M. U.
Vernon, E. G.
Beardmore, R.
Vågbø, C. B.
Chaplin, D.
Gollins, S.
Krokan, H. E.
Lambert, S. A. E.
Paizs, B.
Hartsuiker, E.
author_sort Boeckemeier, L.
collection PubMed
description The Mre11 nuclease is involved in early responses to DNA damage, often mediated by its role in DNA end processing. MRE11 mutations and aberrant expression are associated with carcinogenesis and cancer treatment outcomes. While, in recent years, progress has been made in understanding the role of Mre11 nuclease activities in DNA double-strand break repair, their role during replication has remained elusive. The nucleoside analog gemcitabine, widely used in cancer therapy, acts as a replication chain terminator; for a cell to survive treatment, gemcitabine needs to be removed from replicating DNA. Activities responsible for this removal have, so far, not been identified. We show that Mre11 3′ to 5′ exonuclease activity removes gemcitabine from nascent DNA during replication. This contributes to replication progression and gemcitabine resistance. We thus uncovered a replication-supporting role for Mre11 exonuclease activity, which is distinct from its previously reported detrimental role in uncontrolled resection in recombination-deficient cells.
format Online
Article
Text
id pubmed-7259961
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher American Association for the Advancement of Science
record_format MEDLINE/PubMed
spelling pubmed-72599612020-06-09 Mre11 exonuclease activity removes the chain-terminating nucleoside analog gemcitabine from the nascent strand during DNA replication Boeckemeier, L. Kraehenbuehl, R. Keszthelyi, A. Gasasira, M. U. Vernon, E. G. Beardmore, R. Vågbø, C. B. Chaplin, D. Gollins, S. Krokan, H. E. Lambert, S. A. E. Paizs, B. Hartsuiker, E. Sci Adv Research Articles The Mre11 nuclease is involved in early responses to DNA damage, often mediated by its role in DNA end processing. MRE11 mutations and aberrant expression are associated with carcinogenesis and cancer treatment outcomes. While, in recent years, progress has been made in understanding the role of Mre11 nuclease activities in DNA double-strand break repair, their role during replication has remained elusive. The nucleoside analog gemcitabine, widely used in cancer therapy, acts as a replication chain terminator; for a cell to survive treatment, gemcitabine needs to be removed from replicating DNA. Activities responsible for this removal have, so far, not been identified. We show that Mre11 3′ to 5′ exonuclease activity removes gemcitabine from nascent DNA during replication. This contributes to replication progression and gemcitabine resistance. We thus uncovered a replication-supporting role for Mre11 exonuclease activity, which is distinct from its previously reported detrimental role in uncontrolled resection in recombination-deficient cells. American Association for the Advancement of Science 2020-05-29 /pmc/articles/PMC7259961/ /pubmed/32523988 http://dx.doi.org/10.1126/sciadv.aaz4126 Text en Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY). http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Boeckemeier, L.
Kraehenbuehl, R.
Keszthelyi, A.
Gasasira, M. U.
Vernon, E. G.
Beardmore, R.
Vågbø, C. B.
Chaplin, D.
Gollins, S.
Krokan, H. E.
Lambert, S. A. E.
Paizs, B.
Hartsuiker, E.
Mre11 exonuclease activity removes the chain-terminating nucleoside analog gemcitabine from the nascent strand during DNA replication
title Mre11 exonuclease activity removes the chain-terminating nucleoside analog gemcitabine from the nascent strand during DNA replication
title_full Mre11 exonuclease activity removes the chain-terminating nucleoside analog gemcitabine from the nascent strand during DNA replication
title_fullStr Mre11 exonuclease activity removes the chain-terminating nucleoside analog gemcitabine from the nascent strand during DNA replication
title_full_unstemmed Mre11 exonuclease activity removes the chain-terminating nucleoside analog gemcitabine from the nascent strand during DNA replication
title_short Mre11 exonuclease activity removes the chain-terminating nucleoside analog gemcitabine from the nascent strand during DNA replication
title_sort mre11 exonuclease activity removes the chain-terminating nucleoside analog gemcitabine from the nascent strand during dna replication
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7259961/
https://www.ncbi.nlm.nih.gov/pubmed/32523988
http://dx.doi.org/10.1126/sciadv.aaz4126
work_keys_str_mv AT boeckemeierl mre11exonucleaseactivityremovesthechainterminatingnucleosideanaloggemcitabinefromthenascentstrandduringdnareplication
AT kraehenbuehlr mre11exonucleaseactivityremovesthechainterminatingnucleosideanaloggemcitabinefromthenascentstrandduringdnareplication
AT keszthelyia mre11exonucleaseactivityremovesthechainterminatingnucleosideanaloggemcitabinefromthenascentstrandduringdnareplication
AT gasasiramu mre11exonucleaseactivityremovesthechainterminatingnucleosideanaloggemcitabinefromthenascentstrandduringdnareplication
AT vernoneg mre11exonucleaseactivityremovesthechainterminatingnucleosideanaloggemcitabinefromthenascentstrandduringdnareplication
AT beardmorer mre11exonucleaseactivityremovesthechainterminatingnucleosideanaloggemcitabinefromthenascentstrandduringdnareplication
AT vagbøcb mre11exonucleaseactivityremovesthechainterminatingnucleosideanaloggemcitabinefromthenascentstrandduringdnareplication
AT chaplind mre11exonucleaseactivityremovesthechainterminatingnucleosideanaloggemcitabinefromthenascentstrandduringdnareplication
AT gollinss mre11exonucleaseactivityremovesthechainterminatingnucleosideanaloggemcitabinefromthenascentstrandduringdnareplication
AT krokanhe mre11exonucleaseactivityremovesthechainterminatingnucleosideanaloggemcitabinefromthenascentstrandduringdnareplication
AT lambertsae mre11exonucleaseactivityremovesthechainterminatingnucleosideanaloggemcitabinefromthenascentstrandduringdnareplication
AT paizsb mre11exonucleaseactivityremovesthechainterminatingnucleosideanaloggemcitabinefromthenascentstrandduringdnareplication
AT hartsuikere mre11exonucleaseactivityremovesthechainterminatingnucleosideanaloggemcitabinefromthenascentstrandduringdnareplication