MiR-638 suppresses DNA damage repair by targeting SMC1A expression in terminally differentiated cells.

Mingyang He,Yi Lin,Mingxiong Guo,Chuang Li,Weiwei Zhou,Yunlan Tang,Yi Liu,Guihong Sun

doi:10.18632/aging.100998

Abstract

The reduction of DNA damage repair capacity in terminally differentiated cells may be involved in sensitivity to cancer chemotherapy drugs; however, the underlying molecular mechanism is still not fully understood. Herein, we evaluated the role of miR-638 in the regulation of DNA damage repair in terminally differentiated cells. Our results show that miR-638 expression was up-regulated during cellular terminal differentiation and involved in mediating DNA damage repair processes. Results from a luciferase reporting experiment show that structural maintenance of chromosomes (SMC)1A was a potential target of miR-638; this was verified by western blot assays during cell differentiation and DNA damage induction. Overexpression of miR-638 enhanced the sensitivity of cancer cells to cisplatin, thus reducing cell viability in response to chemotherapy drug treatment. Furthermore, miR-638 overexpression affected DNA damage repair processes by interfering with the recruitment of the DNA damage repair-related protein, γH2AX, to DNA break sites. These findings indicate that miR-638 might act as a sensitizer in cancer chemotherapy and accompany chemotherapy drugs to enhance chemotherapeutic efficacy and to improve the chance of recovery from cancer.

Highlights

Cells regularly encounter various DNA-damaging factors that give rise to genomic DNA damage throughout the life cycle of an organism
A noticeable up-regulation of miR-638 expression was observed in another promyelocytic leukemic cell line, HL-60, which can differentiate into monocytic/ macrophage- or granulocytic-like phenotypes by phorbol myristate acetate (PMA) or dimethyl sulfoxide (DMSO) treatment, respectively (Figure 1B and 1C)
MiR-638 was identified to play a role in regulating target genes (e.g., PLD1, cyclin-dependent kinase 2 (CDK2), p53, PTEN, BRCA1, SOX2, Sp2, TSPAN1) to regulate various cellular processes, including cellular proliferation, cell cycle arrest, apoptosis, differentiation, DNA repair, and tumorigenesis [14, 16, 17, 20, 21, 23, 24, 28, 59]

Summary

Introduction

Cells regularly encounter various DNA-damaging factors that give rise to genomic DNA damage throughout the life cycle of an organism Cells systematically address both endogenous and exogenous sources of DNA damage through their conserved DNA repair and cell cycle checkpoint pathways, which allow cells to maintain genomic stability or prevent cells from entering mitosis. Short-lived terminally differentiated blood cells have reduced DNA repair abilities, due to the miR-24mediated down-regulation of H2AX, which is a key DNA repair protein [8]. These studies indicated that depending on the distinct intercellular microenvironment, diverse terminally differentiated or postmitosis differentiating cells have reduced DNA repair capacities and may employ different DNA damage repair pathways to deal with both endogenous and exogenous sources of DNA damage. The underlying molecular mechanisms behind the reduction of DNA repair capacity in terminally differentiated cells are poorly understood

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