Ng, T. F. | bioRxiv Science

bioRxiv2021

CIP2A is a prime synthetic-lethal target for BRCA-mutated cancers

BRCA1/2-mutated cancer cells must adapt to the genome instability caused by their deficiency in homologous recombination. Identifying and targeting these adaptive mechanisms may provide new therapeutic strategies. Here we present the results of genome-scale CRISPR/Cas9-based synthetic lethality screens in isogenic pairs of BRCA1- and BRCA2-deficient cells that identified the gene encoding CIP2A as essential in a wide range of BRCA1- and BRCA2-mutated cells. Unlike PARP inhibition, CIP2A-deficiency does not cause accumulation of replication-associated DNA lesions that require homologous recombination for their repair. CIP2A is cytoplasmic in interphase but, in mitosis, accumulates at DNA lesions as part of a complex with TOPBP1, a multifunctional genome stability factor. In BRCA-deficient cells, the CIP2A-TOPBP1 complex prevents lethal mis-segregation of acentric chromosomes that arises from impaired DNA synthesis. Finally, physical disruption of the CIP2A-TOPBP1 complex is highly deleterious in BRCA-deficient cells and tumors, indicating that targeting this mitotic chromosome stability process represents an attractive synthetic-lethal therapeutic strategy for BRCA1- and BRCA2-mutated cancers.

cancer biology↗

bioRxiv2019

Identification of \"Missing Link\" Families of Small DNA Tumor Viruses

Polintons (also known as Mavericks) were initially identified as a widespread class of eukaryotic transposons named for their hallmark type B DNA polymerase and retrovirus-like integrase genes. It has since been recognized that many polintons encode possible capsid proteins and viral genome-packaging ATPases similar to those of a diverse range of double-stranded DNA (dsDNA) viruses. This supports the inference that at least some polintons are viruses that remain capable of cell-to-cell spread. At present, there are no polinton-associated capsid protein genes annotated in public sequence databases. To rectify this deficiency, we used a data-mining approach to investigate the distribution and gene content of polinton-like elements and related DNA viruses in animal genomic and metagenomic sequence datasets. The results define a discrete family-like clade of animal-specific viruses with two genus-level divisions. We suggest the family name Adintoviridae, connoting similarities to adenovirus virion proteins and the presence of a retrovirus-like integrase gene. Although adintovirus-class PolB sequences were detected in datasets for fungi and various unicellular eukaryotes, sequences resembling adintovirus virion proteins and accessory genes appear to be restricted to animals. Degraded adintovirus sequences are endogenized into the germlines of a wide range of animals, including humans.

microbiology↗