Correcting an instance of synthetic lethality with a pro-survival sequence

https://doi.org/10.1016/j.bbamcr.2020.118734Get rights and content
Under an Elsevier user license
open archive

Highlights

  • Human LIM domain containing CSRP3 acts as a Bax suppressor and pro-survival protein when heterologously expressed in yeast

  • All four yeast LIM containing sequences are not involved in modulating programmed cell death responses

  • The loss of the LIM containing PXL1 gene in yeast is synthetically lethal with sublethal levels of copper

  • PXL1-copper synthetically lethality is reversed by general pro-survival sequences

Abstract

A human cDNA encoding the LIM domain containing 194 amino acid cysteine and glycine rich protein 3 (CSRP3) was identified as a BAX suppressor in yeast and a pro-survival sequence that abrogated copper mediated regulated cell death (RCD). Yeast lacks a CSRP3 orthologue but it has four LIM sequences, namely RGA1, RGA2, LRG1 and PXL1. These are known regulators of stress responses yet their roles in RCD remain unknown. Given that LIMs interact with other LIMs, we ruled out the possibility that overexpressed yeast LIMs alone could prevent RCD and that CSRP3 functions by acting as a dominant regulator of yeast LIMs. Of interest was the discovery that even though yeast cells lacking the LIM encoding PXL1 had no overt growth defect, it was nevertheless supersensitive to the effects of sublethal levels of copper. Heterologous expression of human CSPR3 as well as the pro-survival 14-3-3 sequence corrected this copper supersensitivity. These results show that the pxl1∆-copper synthetic lethality is likely due to the induction of RCD. This differs from the prevailing model in which synthetic lethality occurs because of specific defects generated by the combined loss of two overlapping but non-essential functions.

Keywords

LIM domain
Homeostasis
Copper
PXL1
Apoptosis
Autophagy

Cited by (0)