Depletion of RNASEH2 Activity Leads to Accumulation of DNA Double-strand Breaks and Reduced Cellular Survivability in T Cell Leukemia

Ghosh, D and Kumari, S and Raghavan, SC (2022) Depletion of RNASEH2 Activity Leads to Accumulation of DNA Double-strand Breaks and Reduced Cellular Survivability in T Cell Leukemia. In: Journal of Molecular Biology, 434 (12).

PDF jou_mol_bio_434-12_2022.pdf - Published Version Restricted to Registered users only Download (2MB) | Request a copy

Abstract

Ribonuclease H2 (RNase H2) is a member of the ribonuclease H family of enzymes involved in removal of RNA from RNA-DNA hybrids as well as ribonucleotides which get misincorporated into the genomic DNA. Recent studies have shown that RNase H2 function is also needed for successful DNA repair through NHEJ events where DNA pol µ uses ribonucleotides during the gap filling stage. Mammalian RNase H2 is composed of three subunits, RNASEH2A, RNASEH2B and RNASEH2C. There have been studies suggesting changes in expression of these genes in various cancers of breast, prostate, colon, liver, and kidney. In this study, we have investigated the functional role of RNASEH2A and RNASEH2B in leukemic T-cells, MOLT4 and Jurkat. shRNA mediated knockdown of RNASEH2A/ RNASEH2B expression led to reduced cell survival and increase in apoptotic cell population. Importantly, knockdown of RNASEH2A or RNASEH2B, led to cell cycle arrest at S phase and increased number of 53BP1 foci due to abrogation of NHEJ. Interestingly, RNASEH2A or RNASEH2B depleted cells showed significantly retarded DSB repair kinetics compared to scrambled shRNA control, when exposed to ionizing radiation suggesting that NHEJ is abrogated due to loss of RNASEH2 activity in T-ALL cells. Thus, we uncover the importance of RNase H2 function in leukemic cells and suggest that it can be targeted for cancer therapy. © 2022 Elsevier Ltd

Item Type:	Journal Article
Publication:	Journal of Molecular Biology
Publisher:	Academic Press
Additional Information:	The copyright for this article belongs to the Academic Press.
Department/Centre:	Division of Biological Sciences > Biochemistry
Date Deposited:	05 Jun 2022 06:11
Last Modified:	05 Jun 2022 06:11
URI:	https://eprints.iisc.ac.in/id/eprint/73104

Actions (login required)

View Item