The Bloom syndrome, caused by mutations in a single gene [BLM (15q26.1)], is a rare genomic instability syndrome. Despite its autosomal recessive transmission, it shows a male dominance, suggesting the possibility of a subgroup with X-linked recessive inheritance. In view of the latest molecular developments achieved in the other genomic instability syndromes, the potential functions of the X c...

Chromosomal destabilization is one end point of the more general phenomenon of genomic instability. We previously established that chro mosomal instability can manifest in clones derived from single progenitor cells several generations after X-irradiation. To understand the potential relationship between chromosomal destabilization and the other end points of genomic instability, we generated a...

Upon DNA damage, histone H2AX is phosphorylated by ataxia-telangiectasia mutated (ATM) and other phosphoinositide 3-kinase-related protein kinases. To elucidate further the potential overlapping and unique functions of ATM and H2AX, we asked whether they have synergistic functions in the development and maintenance of genomic stability by inactivating both genes in mouse germ line. Combined ATM...

Genomic instability is a hallmark of malignant growth that frequently involves mitotic defects associated with centrosome abnormalities. However, the question of whether abnormal centrosomes cause genomic instability or develop secondary to other changes has not been conclusively resolved. Here we show that human papillomavirus (HPV)-16 E7 can induce abnormal centrosome synthesis before the dev...

In humans, Bloom’s Syndrome is caused by a mutation of the RecQ helicase BLM. Patients with Bloom’s Syndrome exhibit a high amount of genomic instability which results in a high incidence of cancer. Though Bloom’s Syndrome has been intensively studied, there are still many questions about the function of BLM which need to be answered. While it is clear that loss of BLM increases genomic instabi...

Human embryonic stem cells (hESC) show great promise for clinical and research applications, but their well-known proneness to genomic instability hampers the development to their full potential. Here, we demonstrate that medium acidification linked to culture density is the main cause of DNA damage and genomic alterations in hESC grown on feeder layers, and this even in the short time span of ...

It is timely to review aspects of DNA repair as there have recently been major advances in this field. These insights have provided information regarding new linkages between DNA repair defects and cancer. Several human repair genes have been identified and cloned, and a direct molecular connection has been established between DNA repair and transcription. The main focus of this review is to ex...

PURPOSE Familial breast cancer represents 5% to 10% of all breast tumors. Mutations in the two known major breast cancer susceptibility genes, BRCA1 and BRCA2, account for a minority of familial breast cancer, whereas families without mutations in these genes (BRCAX group) account for 70% of familial breast cancer cases. EXPERIMENTAL DESIGN To better characterize and define the genomic differ...

Aneuploidy decreases cellular fitness, yet it is also associated with cancer, a disease of enhanced proliferative capacity. To investigate one mechanism by which aneuploidy could contribute to tumorigenesis, we examined the effects of aneuploidy on genomic stability. We analyzed 13 budding yeast strains that carry extra copies of single chromosomes and found that all aneuploid strains exhibited...

Genomic instability is frequently caused by nucleic acid structures termed R-loops that are formed during transcription. Despite their harmful potential, mechanisms that sense, signal, and suppress these structures remain elusive. Here, we report that oscillations in transcription dynamics are a major sensor of R-loops. We show that pausing of RNA polymerase II (RNA Pol II) initiates a signalin...