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Eilers and colleagues report that Aurora-A suppresses transcription–replication conflicts in MYCN-driven neuroblastoma, a vulnerability that can be targeted with a combination of Aurora-A and ATR kinase inhibitors.

Miz1, a Myc-associated transcriptional repressor inhibits cell proliferation. Eilers and colleagues show that the ribosomal protein L23 negatively regulates Miz1 by retaining its activator, nucleophosmin, in the nucleolus.

Oncogenic levels of MYC, the deregulation of which is implicated in many human tumours, are shown to establish a dependence on ARK5, offering insights into potential therapeutic strategies.

Recent publications have indicated that the proto-oncogene MYC is closely involved in DNA replication and S phase checkpoint processes, and have suggested that limiting replication stress is a key function of this protein. How do these findings affect our understanding of how MYC transforms cells?

MYC drives S-phase progression and immune invasion in pancreatic ductal adenocarcinoma (PDAC), but the underlying mechanisms are not fully understood. Here, the authors show that the transcription elongation complex PAF1c controls the competition of different gene sets for RNA polymerase and elongation factors to regulate these MYC-associated mechanisms in PDAC.

Miz1 is a binding partner of the transcription factor c-Myc and a regulator of cell cycle progression. Wolf et al. show that inactivation of Miz1 in the mouse central nervous system results in neurodegeneration, and find that Miz1 is essential for the transcriptional regulation of autophagic flux.

MYC dissociation from active promoters alters its interactions with proteins involved in transcription termination and RNA processing, influencing DNA repair and thus, potentially, tumour cell growth.

Inducing changes in the levels of the MYC oncoprotein is shown to activate and repress specific sets of target genes that are characteristic of tumour cells, providing an insight into the mechanism by which MYC can stimulate tumorigenesis in contrast to its physiological role.

Schmidt et al. show that the translation initiation factor eIF2B5 regulates stress responses and MYC translation to prevent apoptosis, thereby presenting a targetable vulnerability in colorectal cancer.

SCF^Fbw7 mediates the ubiquitylation and degradation of Myc. Now, Myc is also shown to be stabilized by ubquitylation through SCF^β-TrCP. During recovery from S phase arrest, SCF^β-TrCP mediates the addition of a polyubiquitin chain on the Myc amino terminus that is functionally distinct from that formed by Fbw7.

Here the authors identify PHF3 SPOC ___domain as a reader of the phosphorylated RNA polymerase II (Pol II) C-terminal ___domain. They show that PHF3 clusters with Pol II complexes in cells, drives phase separation of Pol II in vitro, and regulates neuronal gene expression and neuronal differentiation.

PIM protein kinases have been known for some time as oncogenes that promote lymphomagenesis together with MYC (c-Myc). It is now reported that PIM1 is a coactivator of MYC, and it phosphorylates serine 10 of histone H3 at MYC target genes. These results may shed new mechanistic light on how PIM1 cooperates with MYC in tumorigenesis.

In yeast, the phosphatase Cdc14 controls mitotic exit. Here the authors show that mammalian CDC14B antagonizes CDK1, to keep the deubiquitinase USP9X unphosphorylated and inactive, and that Wilms’ tumor protein 1 is a substrate for active USP9X that directs mitosis-specific transcription to regulate mitotic survival.

Tripe-negative breast cancers poorly respond to immune checkpoint inhibition therapy, due to their immune-hostile tumour microenvironment. Authors here show that the oncogene MYC plays a pivotal role in suppressing anti-tumour immunity via directly regulating the transcription of interferon signalling genes.

This study describes the mechanism by which Chlamydia trachomatis reprogrammes host glutamine metabolism in a c-Myc-dependent manner. The authors show that glutamine uptake via the SLC15A transporter and glutaminolysis are crucial for peptidoglycan synthesis and Chlamydia replication.

A bifunctional AURORA-A degrader induces the fast and specific degradation of this kinase in cancer cell lines, which enables targeting of non-catalytic, oncogenic functions of AURORA-A resulting in S-phase arrest and rampant apoptosis.

Elevated MYC levels can sensitize tumor cells to apoptosis. In this study, the authors demonstrate that AMPK activation and BCL-2/BCL-X_L inhibition have a synergistic effect on apoptosis, and that together with anti PD-1 therapy they can suppress Myc-driven mammary tumor growth.

In human neuroblastoma tumours, MYCN is engaged in a USP11–BRCA1-dependent manner to suppress the accumulation of stalled RNAPII and induces both the activation and repression of genes.

Sergey Nikolaev, Stylianos Antonarakis and colleagues analyze the genetic architecture of 293 basal cell carcinomas (BCCs) and characterize their mutational landscape. They observe UV signature mutations and identify new driver mutations in MYCN, PTPN14 and LATS1 in BCC.

Unchecked inflammation can lead to tissue damage. Liu and colleagues show that the transcription factor Miz1 recruits the histone deacetylase HDAC1 to restore repression of Cebpd transcription, which is necessary for the termination of LPS-induced inflammatory responses.

In Trp53-mutated hepatocellular carcinoma, conformation-changing aurora kinase A inhibitors disrupt aurora kinase A–MYC interactions, resulting in MYC degradation and suppression of tumor growth.

An in vivo RNAi dropout screen identifies Mapk14 as a new mediator of sorafenib resistance in hepatocellular carcinoma, and Mapk14 inhibition both improves sorafenib therapy and restores sensitivity to sorafenib-resistant tumors.

The MYC oncoproteins are transcription factors, but the molecular mechanism of their oncogenic activity is unclear. MYC proteins promote transcription termination in stress conditions, which is proposed to increase cellular resilience to stress and to promote tumorigenesis independently of changes in the expression of their target genes.