Dis3L2 regulates cell proliferation and tissue growth though a conserved mechanism

Towler, Benjamin P, Pashler, Amy L, Haime, Hope J, Przybyl, Katarzyna M, Viegas, Sandra C, Matos, Rute G, Morley, Simon J, Arraiano, Cecilia M and Newbury, Sarah F (2020) Dis3L2 regulates cell proliferation and tissue growth though a conserved mechanism. PLOS Genetics, 16 (12). a1009297 1-29. ISSN 1553-7390

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Dis3L2 is a highly conserved 3’-5’ exoribonuclease which is mutated in the human overgrowth disorders Perlman syndrome and Wilms’ tumour of the kidney. Using Drosophila melanogaster as a model system, we have generated a new dis3L2 null mutant together with wild-type and nuclease-dead genetic lines in Drosophila to demonstrate that the catalytic activity of Dis3L2 is required to control cell proliferation. To understand the cellular pathways regulated by Dis3L2 to control proliferation, we used RNA-seq on dis3L2 mutant wing discs to show that the imaginal disc growth factor Idgf2 is responsible for driving the wing overgrowth. IDGFs are conserved proteins homologous to human chitinase-like proteins such as CHI3L1/YKL-40 which are implicated in tissue regeneration as well as cancers including colon cancer and non-small cell lung cancer. We also demonstrate that loss of DIS3L2 in human kidney HEK-293T cells results in cell proliferation, illustrating the conservation of this important cell proliferation pathway. Using these human cells, we show that loss of DIS3L2 results in an increase in the PI3-Kinase/AKT signalling pathway, which we subsequently show to contribute towards the proliferation phenotype in Drosophila. Our work therefore provides the first mechanistic explanation for DIS3L2-induced overgrowth in humans and flies and identifies an ancient proliferation pathway controlled by Dis3L2 to regulate cell proliferation and tissue growth.

Item Type: Article
Schools and Departments: Brighton and Sussex Medical School > Clinical and Experimental Medicine
School of Life Sciences > Biochemistry
SWORD Depositor: Mx Elements Account
Depositing User: Mx Elements Account
Date Deposited: 18 Dec 2020 08:44
Last Modified: 25 Feb 2022 14:52
URI: http://sro.sussex.ac.uk/id/eprint/95901

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Project NameSussex Project NumberFunderFunder Ref
Dissecting the cellular pathways controlled by the exoribonuclease Dis3L2 in growth regulationG2431BIOCHEMICAL SOCIETYUnset
Understanding the cellular pathways regulated by Dis3L2 in cell proliferationG2236BBSRC-BIOTECHNOLOGY & BIOLOGICAL SCIENCES RESEARCH COUNCILBB/P021042/1