Fanconi anemia mitosis

WEE1 kinase regulates CDK1 and CDK2 activity to facilitate DNA replication during S-phase and to prevent unscheduled entry into mitosis. WEE1 inhibitors synergize with DNA-damaging agents that arrest cells in S-phase by triggering direct mitotic entry without completing DNA synthesis, resulting in catastrophic chromosome fragmentation and apoptosis. Here, we investigated how WEE1 inhibition could be best exploited for cancer therapy by performing a functional genetic screen to identify novel determinants of sensitivity to WEE1 inhibition...

Fanconi's anemia (FA) is a recessive disease; 16 genes are currently recognized in FA. FA proteins participate in the FA/BRCA pathway that plays a crucial role in the repair of DNA damage induced by crosslinking compounds. Hydroxyurea (HU) is an agent that induces replicative stress by inhibiting ribonucleotide reductase (RNR), which synthesizes deoxyribonucleotide triphosphates (dNTPs) necessary for DNA replication and repair. HU is known to activate the FA pathway; however, its clastogenic effects are not well characterized...

Several helicases function during repair of double-strand breaks and handling of blocked or stalled replication forks to promote pathways that prevent formation of crossovers. Among these are the Bloom syndrome helicase BLM and the Fanconi anemia group M (FANCM) helicase. To better understand functions of these helicases, we compared phenotypes of Drosophila melanogaster Blm and Fancm mutants. As previously reported for BLM, FANCM has roles in responding to several types of DNA damage in preventing mitotic and meiotic crossovers and in promoting the synthesis-dependent strand annealing pathway for repair of a double-strand gap...

Chromosome ends contain nucleoprotein structures known as telomeres. Damage to chromosome ends during interphase elicits a DNA damage response (DDR) resulting in cell cycle arrest. However, little is known regarding the signaling from damaged chromosome ends (designated here as "TIPs") during mitosis. In the present study, we investigated the consequences of DNA damage induced at a single TIP in mitosis. We used laser microirradiation to damage mitotic TIPs or chromosome arms (non-TIPs) in PtK2 kidney epithelial cells...

The Fanconi anemia (FA) pathway is one of the DNA repair systems involved in removal of DNA crosslinks. Proteins which belong to this pathway are crucial to the protection of genetic information, whereas disturbances in their function have serious implications for the whole organism. Biallelic mutations in FA genes are the cause of Fanconi anemia - a genetic disease which manifests itself through numerous congenital abnormalities, chromosomal instability and increased predisposition to cancer. The FA pathway is composed of fifteen proteins...

Fanconi anemia (FA) is a complex heterogenic disorder of genomic instability, bone marrow failure, cancer predisposition, and congenital malformations. The FA signaling network orchestrates the DNA damage recognition and repair in interphase as well as proper execution of mitosis. Loss of FA signaling causes chromosome instability by weakening the spindle assembly checkpoint, disrupting centrosome maintenance, disturbing resolution of ultrafine anaphase bridges, and dysregulating cytokinesis. Thus, the FA genes function as guardians of genome stability throughout the cell cycle...

PURPOSE: As the Fanconi anemia (FA) pathway is required for appropriate cell cycle progression through mitosis and the completion of cell division, the aim of the present study was to determine the destiny of FA cells after irradiation in vitro and to elucidate any difference in radiosensitivity between FA and control cells. MATERIALS AND METHODS: Analyses of phosphorylated histone H2AX (γ-H2AX) foci, micronuclei formation and cell cycle analysis were performed in unirradiated (0 min) and irradiated primary FA fibroblasts and in a control group at different post-irradiation times (30 min, 2 h, 5 h and 24 h)...

AIMS: This study seeks at investigating the cause of hydrocephalus, and at identifying therapeutic targets for the prevention of hydrocephalus. RESULTS: In this study, we show that inactivation of the Foxo3a gene in two mouse models of Fanconi anemia (FA) leads to the development of hydrocephalus in late embryonic stage and after birth. More than 50% of Foxo3a(-/-) Fancc(-/-) or Foxo3a(-/-) Fancd2(-/-) mice die during embryonic development or within 6 months of life as a result of hydrocephalus characterized by cranial distortion, dilation of the ventricular system, reduced thickness of the cerebral cortex, and disorganization of the ependymal cilia and subcommissural organ...

ERCC1 (excision repair cross-complementation group 1) plays essential roles in the removal of DNA intrastrand crosslinks by nucleotide excision repair, and that of DNA interstrand crosslinks by the Fanconi anemia (FA) pathway and homology-directed repair processes (HDR). The function of ERCC1 thus impacts on the DNA damage response (DDR), particularly in anticancer therapy when DNA damaging agents are employed. ERCC1 expression has been proposed as a predictive biomarker of the response to platinum-based therapy...

Fanconi anemia (FA) is a heterogenous genetic disease with a high risk of cancer. The FA proteins are essential for interphase DNA damage repair; however, it is incompletely understood why FA-deficient cells also develop gross aneuploidy, leading to cancer. Here, we systematically evaluated the role of the FA proteins in chromosome segregation through functional RNAi screens and analysis of primary cells from patients with FA. We found that FA signaling is essential for the spindle assembly checkpoint and is therefore required for high-fidelity chromosome segregation and prevention of aneuploidy...

Pulmonary carcinoids comprise a well-differentiated subset of neuroendocrine tumors usually associated with a favorable prognosis, but mechanisms underlying disease progression are poorly understood. In an explorative approach to identify pathways associated with progression, we compared gene expression profiles of tumors from five patients with a favorable and five with a poor disease outcome. Differentially expressed genes were validated using quantitative real-time PCR on 65 carcinoid tumors, in combination with survival analysis...

Fanconi anemia (FA) proteins are known to play roles in the cellular response to DNA interstrand cross-linking lesions; however, several reports have suggested that FA proteins play additional roles. To elucidate novel functions of FA proteins, we used yeast two-hybrid screening to identify binding partners of the Fanconi anemia complementation group A (FANCA) protein. The candidate proteins included never-in-mitosis-gene A (NIMA)-related kinase 2 (Nek2), which functions in the maintenance of centrosome integrity...

Fanconi anemia (FA) is a genome instability syndrome that has been associated with both cancer predisposition and bone marrow failure. FA proteins are involved in cellular response to replication stress in which they coordinate DNA repair with DNA replication and cell-cycle progression. One regulator of the replication stress response is the ATP-dependent DNA translocase FANCM, which we have shown to be hyperphosphorylated in response to various genotoxic agents. However, the significance of this phosphorylation remained unclear...

It has been long speculated that mammalian Rev3 plays an important, yet unknown role(s) during mammalian development, as deletion of Rev3 causes embryonic lethality in mice, whereas no other translesion DNA synthesis polymerases studied to date are required for mouse embryo development. Here, we report that both subunits of Polζ (Rev3 and Rev7) show an unexpected increase in expression during G(2)/M phase, but they localize independently in mitotic cells. Experimental depletion of Rev3 results in a significant increase in anaphase bridges, chromosomal breaks/gaps and common fragile site (CFS) expression, whereas Rev7 depletion primarily causes lagging chromosome defect with no sign of CFS expression...

Cancer cells display numerous abnormal characteristics which are initiated and maintained by elevated mutation rates and genome instability. Chromosomal DNA is continuously surveyed for the presence of damage or blocked replication forks by the DNA Damage Response (DDR) network. The DDR is complex and includes activation of cell cycle checkpoints, DNA repair, gene transcription, and induction of apoptosis. Duplicating a damaged genome is associated with elevated risks to fork collapse and genome instability...

Expression of functional breast cancer susceptibility gene 1 (BRCA1) in human breast and ovarian cancers is associated with resistance to platinum-based chemotherapeutics and poly(ADP ribose) polymerase (PARP) inhibitors. BRCA1 is a nuclear tumor suppressor that is critical for resolving double-strand DNA breaks (DSBs) and interstrand crosslinks (ICLs) by homologous recombination (HR). In vitro, animal and human clinical data have demonstrated that BRCA1-deficient cancers are highly sensitive to ICL-inducing chemotherapeutic agents, are amenable to synthetic lethal approaches that exploit defects in DSB/ICL repair, and may be associated with improved survival...

PURPOSE: Mammography X-rays are known to induce DNA double-strand breaks (DSB) whose error-free recombinational repair requires the function of the tumour repressor genes BRCA1 (breast-cancer-associated gene 1) and BRCA2 (breast-cancer-associated gene 2). Since un- or misrepaired DSB lead to chromosomal anomalies which may promote the development of breast cancer, we have studied the potential of mammography X-rays for immediate and delayed induction of chromosomal anomalies in human primary fibroblasts from BRCA1 and BRCA2 mutation carriers...

The transcriptional repressor Bach1 mediates various stress responses. Despite its role in transcription, Bach1 is predominantly exported to the cytoplasm in a Crm1-dependent manner, but the functional role of its cytoplasmic retention is still unclear. We found that Bach1 was also excluded from mitotic chromatin by a C-terminal cytoplasmic localization sequence dependent and leptomycin B sensitive process. Bach1 depletion resulted in disordered mitotic chromosome alignment, which was rescued by Bach1 mutants lacking the BTB or DNA binding domains, suggesting its transcription-independent mechanism...

Tight regulation of the cell cycle and DNA repair machinery is essential for maintaining genome stability. The APC/CCdh1 ubiquitin ligase complex is a key regulator of protein stability during the G 1 phase of the cell cycle. APC/CCdh1 regulates and promotes the degradation of proteins involved in both cell cycle regulation and DNA repair. In a recent study, we identified a novel APC/CCdh1 substrate, the ubiquitin protease USP1. USP1 is a critical regulator of both the Fanconi anemia (FA) and translesion synthesis (TLS) DNA repair pathways...

Recent data indicate an unexpected requirement for proteins that were hitherto considered to be dedicated to DNA repair to facilitate the faithful disjunction of sister chromatids in anaphase. These include the Bloom's syndrome gene product, BLM and its partners, as well as a number of proteins that are important for preventing Fanconi anemia (FA) in man. As part of an analysis of the roles of these proteins in mitosis, we identified a novel class of anaphase bridge structure, called an ultra-fine anaphase bridge (UFB)...