MiR-223-3p promotes genomic stability of hematopoietic progenitors after radiation

Shi Chen, Gayathri Srinivasan, Aruna Jaiswal, Elizabeth A. Williamson, Lingxiao Li, Dominic Arris, Daohong Zhou, Mingjiang Xu, Robert Hromas

Research output: Contribution to journalArticlepeer-review

Abstract

When hematopoietic cells are overwhelmed with ionizing radiation (IR) DNA damage, the alternative non-homologous end-joining (aNHEJ) repair pathway is activated to repair stressed replication forks. While aNHEJ can rescue cells overwhelmed with DNA damage, it can also mediate chromosomal deletions and fusions, which can cause mis-segregation in mitosis and resultant aneuploidy. We previously reported that a hematopoietic microRNA, miR-223-3p, normally represses aNHEJ. We found that miR-223−/− mice have increased survival of hematopoietic stem and progenitor cells (HSPCs) after sublethal IR. However, this came at the cost of significantly more genomic aberrancies, with miR-223−/− hematopoietic progenitors having increased metaphase aberrancies, including chromothripsis, and increased sequence abnormalities, especially deletions, which is consistent with aNHEJ. These data imply that when an HSPC is faced with substantial DNA damage, it may trade genomic damage for its own survival by choosing the aNHEJ repair pathway, and this choice is regulated in part by miR-223-3p.

Original languageEnglish (US)
Article number104123
JournalExperimental Hematology
Volume129
DOIs
StatePublished - Jan 2024

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Hematology
  • Cancer Research
  • Cell Biology

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