The CIP2A-TOPBP1 complex safeguards chromosomal stability during mitosis.

The accurate repair of DNA double-strand breaks (DSBs), highly toxic DNA lesions, is crucial for genome integrity and is tightly regulated during the cell cycle. In mitosis, cells inactivate DSB repair in favor of a tethering mechanism that stabilizes broken chromosomes until they are repaired in the subsequent cell cycle phases. How this is achieved mechanistically is not yet understood, but the adaptor protein TOPBP1 is critically implicated in this process.

The CIP2A-TOPBP1 axis safeguards chromosome stability and is a synthetic lethal target for BRCA-mutated cancer.

BRCA1/2-mutated cancer cells adapt to the genome instability caused by their deficiency in homologous recombination (HR). Identification of these adaptive mechanisms may provide therapeutic strategies to target tumors caused by the loss of these genes. In the present study, we report genome-scale CRISPR-Cas9 synthetic lethality screens in isogenic pairs of BRCA1- and BRCA2-deficient cells and identify CIP2A as an essential gene in BRCA1- and BRCA2-mutated cells.

Mechanisms of genome stability maintenance during cell division.

During mitosis, chromosomes undergo extensive structural changes resulting in the formation of compact cylindrical bodies and in the termination of the bulk of DNA-dependent metabolic activities. Therefore, DNA lesions that interfere with processes such as DNA replication and transcription in interphase are not expected to pose a major threat to genome stability in mitosis. There are, however, a few exceptions.

MDC1 Interacts with TOPBP1 to Maintain Chromosomal Stability during Mitosis.

In mitosis, cells inactivate DNA double-strand break (DSB) repair pathways to preserve genome stability. However, some early signaling events still occur, such as recruitment of the scaffold protein MDC1 to phosphorylated histone H2AX at DSBs. Yet, it remains unclear whether these events are important for maintaining genome stability during mitosis.

Stathmin Is Required for Normal Mouse Mammary Gland Development and Δ16HER2-Driven Tumorigenesis.

Postnatal development of the mammary gland relies on the maintenance of oriented cell division and apicobasal polarity, both of which are often deregulated in cancer. The microtubule (MT) network contributes to control these processes; however, very little is known about the impact of altered MT dynamics in the development of a complex organ and on the role played by MT-interacting proteins such as stathmin. In this study, we report that female stathmin knock-out (STM KO) mice are unable to nurse their litters due to frank impairment of mammary gland development.

Landscape of CDKN1B Mutations in Luminal Breast Cancer and Other Hormone-Driven Human Tumors.

The gene encodes for the p27 protein, firstly characterized as a cyclin dependent kinase (CDK)-inhibitor. Germline pathogenic variants have been described in hereditary tumors, such as multiple endocrine neoplasia (MEN)-like syndromes and familial prostate cancer. Despite its central role in tumor progression, for a long time it has been proposed that was very rarely somatically mutated in human cancer and that its expression levels were almost exclusively regulated at post-transcriptional level.