The multiple mechanisms of MCL1 in the regulation of cell fate

Abstract

MCL1 (myeloid cell leukemia-1) is a widely recognized pro-survival member of the Bcl-2 (B-cell lymphoma protein 2) family and a promising target for cancer therapy. While the role MCL1 plays in apoptosis is well defined, its participation in emerging non-apoptotic signaling pathways is only beginning to be appreciated. Here, we synthesize studies characterizing MCL1s influence on cell proliferation, DNA damage response, autophagy, calcium handling, and mitochondrial quality control to highlight the broader scope that MCL1 plays in cellular homeostasis regulation. Throughout this review, we discuss which pathways are likely to be impacted by emerging MCL1 inhibitors, as well as highlight non-cancerous disease states that could deploy Bcl-2 homology 3 (BH3)-mimetics in the future.

Fig. 1. MCL1 differentially regulates hematopoietic cell survival and differentiation.

Stem cell differentiation from bone marrow. Blue boxes (MCL1) highlight cell types using in vivo modeling that solely require MCL1 expression for differentiation and/or survival. These cell types undergo a significant amount of apoptosis in vivo when MCL1 is selectively knocked out using genetic manipulation. Red boxes (NE) highlight cell types that exhibit no effect or a non-significant change in cell number compared to control mice when only MCL1 is knocked down.

Fig. 2. MCL1 modulates cell cycle entry and progression.

a In G1 phase, MCL1 binds and inhibits the stability of p18, an inhibitor of the G1/S transition. Decreased expression of p18 promotes cell cycle entry and proliferation in Rb-positive cells. b In S phase, MCL1 binds and inhibits PCNA, inhibiting DNA synthesis and cell cycle progression through G2. c In G2 phase, a nuclear isoform of MCL1 (i.e., snMCL1) binds to CDK1, which prevents the interaction with canonical binding partner, cyclin B. Ultimately, this function of snMCL1 inhibits mitotic completion.

Fig. 3. MCL1 facilitates double-strand break (DSB) DNA repair by stimulating homologous recombination (HR) and inhibiting error-prone non-homologous end joining (NHEJ).

a MCL1 expression in normal tissue. At the sites of DSBs, MCL1 co-localizes and facilitates γH2AX signaling foci, which promotes repair through HR. Furthermore, HR is activated by MCL1 through positive recruitment of the MRN complex, which promotes HR machinery such as BRCA1, ssRPA, and Rad51. MCL1 further inhibits NHEJ through the direct inhibition of the Ku protein complex. b MCL1 inhibition as a therapeutic opportunity for combination therapy in cancer. Upon MCL1 inhibition, HR repair is compromised as highlighted by reduced γH2AX foci at the sites of DBSs and decreased recruitment of BRCA1, ssRPA, and Rad51. 53BP1-RIF1 foci are increased, which promotes error-prone repair through NHEJ. NHEJ is further activated by decreasing the negative MCL1 regulation on Ku. While MCL1 inhibition promotes genomic instability, compromised HR opens a therapeutic window for synthetic lethality approaches that have previously been successful in cancer therapy.

Fig. 4. Membrane-bound MCL1 dysregulates calcium homeostasis and mitochondrial dynamics.

a MCL1 at the OMM binds to pro-apoptotic effector and BH3-only proteins (orange) to resist apoptosis. Upon irreparable cellular stress, MCL1 is downregulated, promoting BAX and/or BAK oligomerization as the rate-limiting step to the apoptotic cascade. b MCL1 binds to VDAC channels (purple) at the OMM, promoting mitochondrial Ca²⁺ uptake, ROS production, and cell migration. c MCL1 binds to DRP-1 (green) at the OMM, modulating mitochondrial fission and fusion. d MCL1 localized to the ER membrane binds and impinges the activity of IP3R channels (blue), promoting basal Ca²⁺ flux from the ER lumen into the cytosol, decreasing ER stores that are required for an array of cellular functions. The dysregulation on IP3R by MCL1 promotes unstimulated Ca²⁺ release, activating cell proliferation. b, d Black arrows indicate the normal flux of calcium ions, whereas green arrows indicate the change in calcium release and uptake in response to MCL1 binding.