Mammalian life depends on two distinct pathways of DNA damage tolerance

Olimpia Alessandra Buoninfante; Bas Pilzecker; Aldo Spanjaard; Dani?l de Groot; Stefan Prekovic; Ji-Ying Song; Cor Lieftink; Matilda Ayidah; Colin E. J. Pritchard; Judith Vivi?; Kathleen E. McGrath; Ivo J. Huijbers; Sjaak Philipsen; Marieke von Lindern; Wilbert Zwart; Roderick L. Beijersbergen; James Palis; Paul C. M. van den Berk; Heinz Jacobs

doi:https://doi.org/10.1073/pnas.2216055120

Mammalian life depends on two distinct pathways of DNA damage tolerance

Olimpia Alessandra Buoninfante, Bas Pilzecker, Aldo Spanjaard, Dani?l de Groot, Stefan Prekovic, Ji-Ying Song, Cor Lieftink, Matilda Ayidah, Colin E. J. Pritchard, Judith Vivi?, Kathleen E. McGrath, Ivo J. Huijbers, Sjaak Philipsen, Marieke von Lindern, Wilbert Zwart, Roderick L. Beijersbergen, James Palis, Paul C. M. van den Berk, Heinz Jacobs

Research output: Contribution to journal › Article › Academic › peer-review

2 Citations (Scopus)

Abstract

DNA damage threatens genomic integrity and instigates stem cell failure. To bypass genotoxic lesions during replication, cells employ DNA damage tolerance (DDT), which is regulated via PCNA ubiquitination and REV1. DDT is conserved in all domains of life, yet its relevance in mammals remains unclear. Here, we show that inactivation of both PCNA-ubiquitination and REV1 results in embryonic and adult lethality, and the accumulation of DNA damage in hematopoietic stem and progenitor cells (HSPCs) that ultimately resulted in their depletion. Our results reveal the crucial relevance of DDT in the maintenance of stem cell compartments and mammalian life in unperturbed conditions.

Original language	English
Article number	e2216055120
Journal	PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume	120
Issue number	4
DOIs	https://doi.org/10.1073/pnas.2216055120
Publication status	Published - 24 Jan 2023

Keywords

DNA damage response (DDR)
DNA damage tolerance (DDT)
embryonic lethality
erythropoiesis
hematopoietic stem cells

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Buoninfante, O. A., Pilzecker, B., Spanjaard, A., de Groot, D., Prekovic, S., Song, J.-Y., Lieftink, C., Ayidah, M., Pritchard, C. E. J., Vivi?, J., McGrath, K. E., Huijbers, I. J., Philipsen, S., von Lindern, M., Zwart, W., Beijersbergen, R. L., Palis, J., van den Berk, P. C. M., & Jacobs, H. (2023). Mammalian life depends on two distinct pathways of DNA damage tolerance. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 120(4), Article e2216055120. https://doi.org/10.1073/pnas.2216055120

@article{7717d4851ce04c3f8508e0812ea37a64,

title = "Mammalian life depends on two distinct pathways of DNA damage tolerance",

abstract = "DNA damage threatens genomic integrity and instigates stem cell failure. To bypass genotoxic lesions during replication, cells employ DNA damage tolerance (DDT), which is regulated via PCNA ubiquitination and REV1. DDT is conserved in all domains of life, yet its relevance in mammals remains unclear. Here, we show that inactivation of both PCNA-ubiquitination and REV1 results in embryonic and adult lethality, and the accumulation of DNA damage in hematopoietic stem and progenitor cells (HSPCs) that ultimately resulted in their depletion. Our results reveal the crucial relevance of DDT in the maintenance of stem cell compartments and mammalian life in unperturbed conditions.",

keywords = "DNA damage response (DDR), DNA damage tolerance (DDT), embryonic lethality, erythropoiesis, hematopoietic stem cells",

author = "Buoninfante, {Olimpia Alessandra} and Bas Pilzecker and Aldo Spanjaard and {de Groot}, Dani?l and Stefan Prekovic and Ji-Ying Song and Cor Lieftink and Matilda Ayidah and Pritchard, {Colin E. J.} and Judith Vivi? and McGrath, {Kathleen E.} and Huijbers, {Ivo J.} and Sjaak Philipsen and {von Lindern}, Marieke and Wilbert Zwart and Beijersbergen, {Roderick L.} and James Palis and {van den Berk}, {Paul C. M.} and Heinz Jacobs",

note = "Funding Information: We like to thank N. Wit and F. Alemdehy for comments on the manuscript, members of the FACS facility for assistance during sorting and flow cytometric analysis, the biotechnical staff of the Netherlands Cancer Institute - Antoni van Leeuwenhoek Mouse Clinic for Cancer and Aging (MCCA) for biotechnical support, C. G{\"o}bel for help with ChIP-Seq experiments, and all the members of mouse facility for assistance in maintenance of mice. Portions of this work were developed from the doctoral dissertation of O.A.B. Publisher Copyright: Copyright {\textcopyright} 2023 the Author(s).",

year = "2023",

month = jan,

day = "24",

doi = "https://doi.org/10.1073/pnas.2216055120",

language = "English",

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journal = "PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA",

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Buoninfante, OA, Pilzecker, B, Spanjaard, A, de Groot, D, Prekovic, S, Song, J-Y, Lieftink, C, Ayidah, M, Pritchard, CEJ, Vivi?, J, McGrath, KE, Huijbers, IJ, Philipsen, S, von Lindern, M, Zwart, W, Beijersbergen, RL, Palis, J, van den Berk, PCM & Jacobs, H 2023, 'Mammalian life depends on two distinct pathways of DNA damage tolerance', PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, vol. 120, no. 4, e2216055120. https://doi.org/10.1073/pnas.2216055120

TY - JOUR

T1 - Mammalian life depends on two distinct pathways of DNA damage tolerance

AU - Buoninfante, Olimpia Alessandra

AU - Pilzecker, Bas

AU - Spanjaard, Aldo

AU - de Groot, Dani?l

AU - Prekovic, Stefan

AU - Song, Ji-Ying

AU - Lieftink, Cor

AU - Ayidah, Matilda

AU - Pritchard, Colin E. J.

AU - Vivi?, Judith

AU - McGrath, Kathleen E.

AU - Huijbers, Ivo J.

AU - Philipsen, Sjaak

AU - von Lindern, Marieke

AU - Zwart, Wilbert

AU - Beijersbergen, Roderick L.

AU - Palis, James

AU - van den Berk, Paul C. M.

AU - Jacobs, Heinz

N1 - Funding Information: We like to thank N. Wit and F. Alemdehy for comments on the manuscript, members of the FACS facility for assistance during sorting and flow cytometric analysis, the biotechnical staff of the Netherlands Cancer Institute - Antoni van Leeuwenhoek Mouse Clinic for Cancer and Aging (MCCA) for biotechnical support, C. Göbel for help with ChIP-Seq experiments, and all the members of mouse facility for assistance in maintenance of mice. Portions of this work were developed from the doctoral dissertation of O.A.B. Publisher Copyright: Copyright © 2023 the Author(s).

PY - 2023/1/24

Y1 - 2023/1/24

N2 - DNA damage threatens genomic integrity and instigates stem cell failure. To bypass genotoxic lesions during replication, cells employ DNA damage tolerance (DDT), which is regulated via PCNA ubiquitination and REV1. DDT is conserved in all domains of life, yet its relevance in mammals remains unclear. Here, we show that inactivation of both PCNA-ubiquitination and REV1 results in embryonic and adult lethality, and the accumulation of DNA damage in hematopoietic stem and progenitor cells (HSPCs) that ultimately resulted in their depletion. Our results reveal the crucial relevance of DDT in the maintenance of stem cell compartments and mammalian life in unperturbed conditions.

AB - DNA damage threatens genomic integrity and instigates stem cell failure. To bypass genotoxic lesions during replication, cells employ DNA damage tolerance (DDT), which is regulated via PCNA ubiquitination and REV1. DDT is conserved in all domains of life, yet its relevance in mammals remains unclear. Here, we show that inactivation of both PCNA-ubiquitination and REV1 results in embryonic and adult lethality, and the accumulation of DNA damage in hematopoietic stem and progenitor cells (HSPCs) that ultimately resulted in their depletion. Our results reveal the crucial relevance of DDT in the maintenance of stem cell compartments and mammalian life in unperturbed conditions.

KW - DNA damage response (DDR)

KW - DNA damage tolerance (DDT)

KW - embryonic lethality

KW - erythropoiesis

KW - hematopoietic stem cells

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U2 - https://doi.org/10.1073/pnas.2216055120

DO - https://doi.org/10.1073/pnas.2216055120

M3 - Article

C2 - 36669105

SN - 0027-8424

VL - 120

JO - PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

JF - PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

IS - 4

M1 - e2216055120

ER -

Mammalian life depends on two distinct pathways of DNA damage tolerance

Abstract

Keywords

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