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

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number6071
JournalScientific Reports
Volume8
Issue number1
DOIs
StatePublished - 1 Dec 2018

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