Modelling the distinct roles of epithelial and stromal androgen receptor in the regulation of prostate epithelial dynamics.

The prostate is an androgen-responsive organ, but the complex cellular and molecular interactions that mediate these responses remain incompletely defined. Here, I synthesise the existing literature to derive a simple conceptual framework describing the androgen-dependent regulation of prostate epithelial dynamics. In this framework, epithelial androgen receptor (AR) cell-autonomously controls luminal cell height, whereas stromal AR regulates the synthesis of growth factors that promote luminal cell survival and proliferation.

Winged helix domains with unknown function in Hel308 and related helicases.

Hel308 is a superfamily 2 helicase/translocase that is conserved throughout archaea and in some eukaryotes for repair of genotoxic lesions such as ICLs (interstrand DNA cross-links). Atomic structures of archaeal Hel308 have allowed mechanistic insights into ATPase and helicase functions, but have also highlighted structures that currently lack a known function, such as an unexpected WH (winged helix) domain. This domain and similar overall protein structural organization was also identified in other superfamily 2 helicases that process RNA molecules in eukaryotes: Brr2, Mtr4 and Prp43p.

Physical interaction between archaeal DNA repair helicase Hel308 and Replication Protein A (RPA).

Hel308 is a super-family 2 helicase in archaea with homologues in higher eukaryotes (HelQ and PolQ) that contribute to repair of DNA strand crosslinks (ICLs). However, the contribution of Hel308 to repair processes in archaea is far from clear, including how it co-operates with other proteins of DNA replication, repair and recombination. In this study we identified a physical interaction of Hel308 with RPA.

Molecular biology of Hel308 helicase in archaea.

Hel308 is an SF2 (superfamily 2) helicase with clear homologues in metazoans and archaea, but not in fungi or bacteria. Evidence from biochemistry and genetics implicates Hel308 in remodelling compromised replication forks. In the last 4 years, significant advances have been made in understanding the biochemistry of archaeal Hel308, most recently through atomic structures from cren- and eury-archaea.

Archaeal Hel308 domain V couples DNA binding to ATP hydrolysis and positions DNA for unwinding over the helicase ratchet.

Hel308 and PolQ are paralogues with roles promoting genome stability in archaea and higher eukaryotes. The context in which they act is not clear, although Hel308 helicase from archaea may interact with abnormal replication forks. The atomic structure of archaeal Hel308 from Archaeoglobus fulgidus in complex with DNA was recently reported and has given insights into the mechanisms of superfamily-2 helicases generally.