DIS3 isoforms vary in their endoribonuclease activity and are differentially expressed within haematological cancers

Robinson, Sophie R, Viegas, Sandra C, Matos, Rute G, Domingues, Susana, Bedir, Marisa, Stewart, Helen J S, Chevassut, Timothy, Oliver, Antony W, Arraiano, Cecilia M and Newbury, Sarah F (2018) DIS3 isoforms vary in their endoribonuclease activity and are differentially expressed within haematological cancers. Biochemical Journal, 475 (12). pp. 2091-2105. ISSN 0264-6021

[img] PDF - Published Version
Available under License Creative Commons Attribution.

Download (12MB)
[img] PDF (Research article) - Accepted Version
Download (1MB)


DIS3 is the catalytic subunit of the exosome, a protein complex involved in the 3’ to 5’ degradation of RNAs. DIS3 is a highly conserved exoribonuclease, also known as Rrp44. Global sequencing studies have identified DIS3 as being mutated in a range of cancers, with a considerable incidence in multiple myeloma. In this work, we have identified two proteincoding isoforms of DIS3. Both isoforms are functionally relevant and result from alternative splicing. They differ from each other in the size of their N-terminal PIN domain, which has been shown to have endoribonuclease activity and tether DIS3 to the exosome. Isoform 1 encodes a full-length PIN domain, whereas the PIN domain of isoform 2 is shorter and is
missing a segment with conserved amino-acids. We have carried out biochemical activity assays on both isoforms of full-length DIS3 as well as the isolated PIN domains. We find that isoform 2, despite missing part of the PIN domain, has greater endonuclease activity compared to isoform 1. Examination of the available structural information allows us to provide a hypothesis to explain this altered behaviour. Our results also show that multiple myeloma patient cells and all cancer cell lines tested have higher levels of isoform 1 compared to isoform 2 whereas Acute Myeloid Leukemia (AML) and chronic myelomonocytic leukaemia (CMML) patient cells and samples from healthy donors have similar levels of isoforms 1 and 2. Together, our data indicate that significant changes in the ratios of the two isoforms could be symptomatic of haematological cancers.

Item Type: Article
Schools and Departments: Brighton and Sussex Medical School > Brighton and Sussex Medical School
Brighton and Sussex Medical School > Clinical and Experimental Medicine
School of Life Sciences > Sussex Centre for Genome Damage and Stability
Research Centres and Groups: Haematology Research Group
Subjects: R Medicine
R Medicine > RC Internal medicine
R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology Including cancer and carcinogens
Depositing User: Timothy Chevassut
Date Deposited: 04 Jun 2018 10:17
Last Modified: 18 Feb 2022 16:10
URI: http://sro.sussex.ac.uk/id/eprint/46151

View download statistics for this item

📧 Request an update
Project NameSussex Project NumberFunderFunder Ref
Drug-induced selective lethality in populations of DNMT3A knockdown cellsG2782WELLCOME TRUST218435/Z/19/Z
How does SARS CoV-2 infect blood vessels?G3146UK RESEARCH AND INNOVATIONMR/V036750/1
In vitro modelling and therapeutic targeting of tumour cell migration in chronic lymphocytic leukaemia.G2544BLOODWISE18005
Mining the Wnt signalling-responsive surfaceome for drug targets in acute myeloid leukaemiaG3090WELLCOME TRUSTUnset
Modelling and targeting Acute Myeloid Leukaemia cells in the Bone Marrow protective nicheG3106SUSSEX CANCER FUND FOR TREATMENT AND RESEARCHUnset
Structural Biology of DNA Damage Response and Repair MechanismsG2176CANCER RESEARCH UKC302/A24386