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  • MARCH5-dependent degradation of MCL1/NOXA complexes defines susceptibility to antimitotic drug treatment.

MARCH5-dependent degradation of MCL1/NOXA complexes defines susceptibility to antimitotic drug treatment.

Cell death and differentiation (2020-02-06)
Manuel D Haschka, Gerlinde Karbon, Claudia Soratroi, Katelyn L O'Neill, Xu Luo, Andreas Villunger
ABSTRACT

Cells experiencing delays in mitotic progression are prone to undergo apoptosis unless they can exit mitosis before proapoptotic factors reach a critical threshold. Microtubule targeting agents (MTAs) arrest cells in mitosis and induce apoptotic cell death engaging the BCL2 network. Degradation of the antiapoptotic BCL2 family member MCL-1 is considered to set the time until onset of apoptosis upon MTA treatment. MCL1 degradation involves its interaction with one of its key binding partners, the proapoptotic BH3-only protein NOXA. Here, we report that the mitochondria-associated E3-ligase MARCH5, best known for its role in mitochondrial quality control and regulation of components of the mitochondrial fission machinery, controls the levels of MCL1/NOXA protein complexes in steady state as well as during mitotic arrest. Inhibition of MARCH5 function sensitizes cancer cells to the proapoptotic effects of MTAs by the accumulation of NOXA and primes cancer cells that may undergo slippage to escape death in mitosis to cell death in the next G1 phase. We propose that inhibition of MARCH5 may be a suitable strategy to sensitize cancer cells to antimitotic drug treatment.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Cycloheximide, Biotechnology Performance Certified
Sigma-Aldrich
Albumin, Bovine Serum, Fraction V, Low Heavy Metals
Sigma-Aldrich
Anti-March5 Antibody, serum, from rabbit
Millipore
Skim Milk Powder, suitable for microbiology