Mechanisms of disease: from stem cells to colorectal cancer.

Over the past decade, the advances in our understanding of stem cell biology and the role of stem cells in diseases, such as colorectal cancer, have been remarkable. In particular, discoveries related to the control of stem cell proliferation and how dysregulation of proliferation leads to oncogenesis have been foremost. For intestinal stem cells, the WNT family of growth factors, and events such as the regulation of the nuclear localization of beta-catenin, seem to be central to normal homeostasis, and mutations in the components of these pathways seem to lead to the development of colorectal cancer.

Distinct modes of ATR activation after replication stress and DNA double-strand breaks in Caenorhabditis elegans.

ATM and ATR are key components of the DNA damage checkpoint. ATR primarily responds to UV damage and replication stress, yet may also function with ATM in the checkpoint response to DNA double-strand breaks (DSBs), although this is less clear. Here, we show that atl-1 (Caenorhabditis elegans ATR) and rad-5/clk-2 prevent mitotic catastrophe, function in the S-phase checkpoint and also cooperate with atm-1 in the checkpoint response to DSBs after ionizing radiation (IR) to induce cell cycle arrest or apoptosis via the cep-1(p53)/egl-1 pathway.

Crystal structure of RecBCD enzyme reveals a machine for processing DNA breaks.

RecBCD is a multi-functional enzyme complex that processes DNA ends resulting from a double-strand break. RecBCD is a bipolar helicase that splits the duplex into its component strands and digests them until encountering a recombinational hotspot (Chi site). The nuclease activity is then attenuated and RecBCD loads RecA onto the 3' tail of the DNA.

Crystallization of the xeroderma pigmentosum group F endonuclease from Aeropyrum pernix.

The xeroderma pigmentosa group F protein (XPF) is a founding member of a family of 3'-flap endonucleases that play an essential role in nucleotide-excision repair, DNA replication and recombination. The XPF gene has been cloned from Aeropyrum pernix, encoding a 254-residue protein (apXPF). Recombinant protein was produced in Escherichia coli and purified by three chromatographic steps.

BRCA1/BARD1 orthologs required for DNA repair in Caenorhabditis elegans.

Inherited germline mutations in the tumor suppressor gene BRCA1 predispose individuals to early onset breast and ovarian cancer. BRCA1 together with its structurally related partner BARD1 is required for homologous recombination and DNA double-strand break repair, but how they perform these functions remains elusive. As part of a comprehensive search for DNA repair genes in C.

Biochemical analysis of components of the pre-replication complex of Archaeoglobus fulgidus.

The eukaryotic pre-replication complex is assembled at replication origins in a reaction called licensing. Licensing involves the interactions of a variety of proteins including the origin recognition complex (ORC), Cdc6 and the Mcm2-7 helicase, homologues of which are also found in archaea. The euryarchaeote Archaeoglobus fulgidus encodes two genes with homology to Orc/Cdc6 and a single Mcm homologue.