Attenuated DNA damage responses and increased apoptosis characterize human hematopoietic stem cells exposed to irradiation

Abstract Failure to precisely repair DNA damage in self-renewing Hematopoietic Stem and early Progenitor Cells (HSPCs) can disrupt normal hematopoiesis and promote leukemogenesis. Although HSPCs are widely considered a target of ionizing radiation (IR)-induced hematopoietic injury, definitive data r...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Shahar Biechonski, Leonid Olender, Adi Zipin-Roitman, Muhammad Yassin, Nasma Aqaqe, Victoria Marcu-Malina, Melanie Rall-Scharpf, Magan Trottier, M. Stephen Meyn, Lisa Wiesmüller, Katia Beider, Yael Raz, Dan Grisaru, Arnon Nagler, Michael Milyavsky
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/9313fac1c8ce4adb8917c5a6468462c9
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:9313fac1c8ce4adb8917c5a6468462c9
record_format	dspace
spelling	oai:doaj.org-article:9313fac1c8ce4adb8917c5a6468462c92021-12-02T15:07:44ZAttenuated DNA damage responses and increased apoptosis characterize human hematopoietic stem cells exposed to irradiation10.1038/s41598-018-24440-w2045-2322https://doaj.org/article/9313fac1c8ce4adb8917c5a6468462c92018-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-24440-whttps://doaj.org/toc/2045-2322Abstract Failure to precisely repair DNA damage in self-renewing Hematopoietic Stem and early Progenitor Cells (HSPCs) can disrupt normal hematopoiesis and promote leukemogenesis. Although HSPCs are widely considered a target of ionizing radiation (IR)-induced hematopoietic injury, definitive data regarding cell death, DNA repair, and genomic stability in these rare quiescent cells are scarce. We found that irradiated HSPCs, but not lineage-committed progenitors (CPs), undergo rapid ATM-dependent apoptosis, which is suppressed upon interaction with bone-marrow stroma cells. Using DNA repair reporters to quantify mutagenic Non-Homologous End Joining (NHEJ) processes, we found that HSPCs exhibit reduced NHEJ activities in comparison with CPs. HSPC-stroma interactions did not affect the NHEJ capacity of HSPCs, emphasizing its cell autonomous regulation. We noted diminished expression of multiple double strand break (DSB) repair transcripts along with more persistent 53BP1 foci in irradiated HSPCs in comparison with CPs, which can account for low NHEJ activity and its distinct control in HSPCs. Finally, we documented clonal chromosomal aberrations in 10% of IR-surviving HSPCs. Taken together, our results revealed potential mechanisms contributing to the inherent susceptibility of human HSPC to the cytotoxic and mutagenic effects of DNA damage.Shahar BiechonskiLeonid OlenderAdi Zipin-RoitmanMuhammad YassinNasma AqaqeVictoria Marcu-MalinaMelanie Rall-ScharpfMagan TrottierM. Stephen MeynLisa WiesmüllerKatia BeiderYael RazDan GrisaruArnon NaglerMichael MilyavskyNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-13 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Shahar Biechonski Leonid Olender Adi Zipin-Roitman Muhammad Yassin Nasma Aqaqe Victoria Marcu-Malina Melanie Rall-Scharpf Magan Trottier M. Stephen Meyn Lisa Wiesmüller Katia Beider Yael Raz Dan Grisaru Arnon Nagler Michael Milyavsky Attenuated DNA damage responses and increased apoptosis characterize human hematopoietic stem cells exposed to irradiation
description	Abstract Failure to precisely repair DNA damage in self-renewing Hematopoietic Stem and early Progenitor Cells (HSPCs) can disrupt normal hematopoiesis and promote leukemogenesis. Although HSPCs are widely considered a target of ionizing radiation (IR)-induced hematopoietic injury, definitive data regarding cell death, DNA repair, and genomic stability in these rare quiescent cells are scarce. We found that irradiated HSPCs, but not lineage-committed progenitors (CPs), undergo rapid ATM-dependent apoptosis, which is suppressed upon interaction with bone-marrow stroma cells. Using DNA repair reporters to quantify mutagenic Non-Homologous End Joining (NHEJ) processes, we found that HSPCs exhibit reduced NHEJ activities in comparison with CPs. HSPC-stroma interactions did not affect the NHEJ capacity of HSPCs, emphasizing its cell autonomous regulation. We noted diminished expression of multiple double strand break (DSB) repair transcripts along with more persistent 53BP1 foci in irradiated HSPCs in comparison with CPs, which can account for low NHEJ activity and its distinct control in HSPCs. Finally, we documented clonal chromosomal aberrations in 10% of IR-surviving HSPCs. Taken together, our results revealed potential mechanisms contributing to the inherent susceptibility of human HSPC to the cytotoxic and mutagenic effects of DNA damage.
format	article
author	Shahar Biechonski Leonid Olender Adi Zipin-Roitman Muhammad Yassin Nasma Aqaqe Victoria Marcu-Malina Melanie Rall-Scharpf Magan Trottier M. Stephen Meyn Lisa Wiesmüller Katia Beider Yael Raz Dan Grisaru Arnon Nagler Michael Milyavsky
author_facet	Shahar Biechonski Leonid Olender Adi Zipin-Roitman Muhammad Yassin Nasma Aqaqe Victoria Marcu-Malina Melanie Rall-Scharpf Magan Trottier M. Stephen Meyn Lisa Wiesmüller Katia Beider Yael Raz Dan Grisaru Arnon Nagler Michael Milyavsky
author_sort	Shahar Biechonski
title	Attenuated DNA damage responses and increased apoptosis characterize human hematopoietic stem cells exposed to irradiation
title_short	Attenuated DNA damage responses and increased apoptosis characterize human hematopoietic stem cells exposed to irradiation
title_full	Attenuated DNA damage responses and increased apoptosis characterize human hematopoietic stem cells exposed to irradiation
title_fullStr	Attenuated DNA damage responses and increased apoptosis characterize human hematopoietic stem cells exposed to irradiation
title_full_unstemmed	Attenuated DNA damage responses and increased apoptosis characterize human hematopoietic stem cells exposed to irradiation
title_sort	attenuated dna damage responses and increased apoptosis characterize human hematopoietic stem cells exposed to irradiation
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/9313fac1c8ce4adb8917c5a6468462c9
work_keys_str_mv	AT shaharbiechonski attenuateddnadamageresponsesandincreasedapoptosischaracterizehumanhematopoieticstemcellsexposedtoirradiation AT leonidolender attenuateddnadamageresponsesandincreasedapoptosischaracterizehumanhematopoieticstemcellsexposedtoirradiation AT adizipinroitman attenuateddnadamageresponsesandincreasedapoptosischaracterizehumanhematopoieticstemcellsexposedtoirradiation AT muhammadyassin attenuateddnadamageresponsesandincreasedapoptosischaracterizehumanhematopoieticstemcellsexposedtoirradiation AT nasmaaqaqe attenuateddnadamageresponsesandincreasedapoptosischaracterizehumanhematopoieticstemcellsexposedtoirradiation AT victoriamarcumalina attenuateddnadamageresponsesandincreasedapoptosischaracterizehumanhematopoieticstemcellsexposedtoirradiation AT melanierallscharpf attenuateddnadamageresponsesandincreasedapoptosischaracterizehumanhematopoieticstemcellsexposedtoirradiation AT magantrottier attenuateddnadamageresponsesandincreasedapoptosischaracterizehumanhematopoieticstemcellsexposedtoirradiation AT mstephenmeyn attenuateddnadamageresponsesandincreasedapoptosischaracterizehumanhematopoieticstemcellsexposedtoirradiation AT lisawiesmuller attenuateddnadamageresponsesandincreasedapoptosischaracterizehumanhematopoieticstemcellsexposedtoirradiation AT katiabeider attenuateddnadamageresponsesandincreasedapoptosischaracterizehumanhematopoieticstemcellsexposedtoirradiation AT yaelraz attenuateddnadamageresponsesandincreasedapoptosischaracterizehumanhematopoieticstemcellsexposedtoirradiation AT dangrisaru attenuateddnadamageresponsesandincreasedapoptosischaracterizehumanhematopoieticstemcellsexposedtoirradiation AT arnonnagler attenuateddnadamageresponsesandincreasedapoptosischaracterizehumanhematopoieticstemcellsexposedtoirradiation AT michaelmilyavsky attenuateddnadamageresponsesandincreasedapoptosischaracterizehumanhematopoieticstemcellsexposedtoirradiation
_version_	1718388403656982528

Attenuated DNA damage responses and increased apoptosis characterize human hematopoietic stem cells exposed to irradiation

Ejemplares similares