variants underlying X-linked intellectual disability disrupt protein function via distinct mechanisms.

Neurodevelopmental disorders with intellectual disability (ND/ID) are a heterogeneous group of diseases driving lifelong deficits in cognition and behavior with no definitive cure. X-linked intellectual disability disorder 105 (XLID105, #300984; OMIM) is a ND/ID driven by hemizygous variants in the gene encoding a protein deubiquitylase with a role in cell proliferation and neural development. Currently, only four genetically diagnosed individuals from two unrelated families have been described with limited clinical data.

Regulation of Cyclin D1 Degradation by Ubiquitin-Specific Protease 27X Is Critical for Cancer Cell Proliferation and Tumor Growth.

Unlabelled: Cyclin D1 (CCND1) is a critical regulator of cell proliferation and its overexpression has been linked to the development and progression of several malignancies. CCND1 overexpression is recognized as a major mechanism of therapy resistance in several cancers; tumors that rely on CCND1 overexpression to evade cancer therapy are extremely sensitive to its ablation. Therefore, targeting CCND1 is a promising strategy for preventing tumor progression and combating therapy resistance in cancer patients.

New sheriff in town: Cyclic peptide inhibitors of a DUB module.

In this issue of Cell Chemical Biology, Morgan et al. (2021) show that cyclic peptides can be potent and highly specific inhibitors for deubiquitinating enzymes. This study identifies the first selective inhibitors of the cancer-associated ubiquitin-specific protease 22 (USP22).

Overexpression Leads to Aberrant Signal Transduction of Cancer-Related Pathways but Is Not Sufficient to Drive Tumor Formation in Mice.

overexpression is observed in several human cancers and is correlated with poor patient outcomes. The molecular basis underlying this correlation is not clear. is the catalytic subunit of the deubiquitylation module in the SAGA histone-modifying complex, which regulates gene transcription.

Regulation of Histone Ubiquitination in Response to DNA Double Strand Breaks.

Eukaryotic cells are constantly exposed to both endogenous and exogenous stressors that promote the induction of DNA damage. Of this damage, double strand breaks (DSBs) are the most lethal and must be efficiently repaired in order to maintain genomic integrity. Repair of DSBs occurs primarily through one of two major pathways: non-homologous end joining (NHEJ) or homologous recombination (HR).