Single-stranded DNA-binding protein hSSB1 is critical for genomic stability

Single-strand DNA (ssDNA)-binding proteins (SSBs) are ubiquitous and essential for a wide variety of DNA metabolic processes, including DNA replication, recombination, DNA damage detection and repair1. SSBs have multiple roles in binding and sequestering ssDNA, detecting DNA damage, stimulating nucleases, helicases and strand-exchange proteins, activating transcription and mediating protein–protein interactions. In eukaryotes, the major SSB, replication protein A (RPA), is a heterotrimer1. Here we describe a second human SSB (hSSB1), with a domain organization closer to the archaeal SSB than to RPA. Ataxia telangiectasia mutated (ATM) kinase phosphorylates hSSB1 in response to DNA double-strand breaks (DSBs). This phosphorylation event is required for DNA damage-induced stabilization of hSSB1. Upon induction of DNA damage, hSSB1 accumulates in the nucleus and forms distinct foci independent of cell-cycle phase. These foci co-localize with other known repair proteins. In contrast to RPA, hSSB1 does not localize to replication foci in S-phase cells and hSSB1 deficiency does not influence S-phase progression. Depletion of hSSB1 abrogates the cellular response to DSBs, including activation of ATM and phosphorylation of ATM targets after ionizing radiation. Cells deficient in hSSB1 exhibit increased radiosensitivity, defective checkpoint activation and enhanced genomic instability coupled with a diminished capacity for DNA repair. These findings establish that hSSB1 influences diverse endpoints in the cellular DNA damage response.

Attach the correct warning statement

Practitioners will be aware that s 366 (1) of the Property Agents and Motor Dealers Act 2000 provides that a relevant contract must have attached, as its first or top sheet, a warning statement in the approved form. A failure to attach a warning statement in the prescribed manner triggers a right of termination in the buyer. The factual circumstances in Devine Ltd v Timbs [2004] QSC 24 are indicative of the problems that may arise in the construction of this statutory provision. The application concerned put and call option agreements entered into concerning 4 lots. The agreements, in identical terms, were signed before the applicant seller had completed a proposed residential apartment building. In each case the option agreement provided that the agreement was not binding on the seller until and unless the purchaser returned to the seller, amongst other things, two copies of the warning statement under the Property Agents and Motor Dealers Ac 2000 signed by the purchaser and two copies of the contract document signed by the purchaser. The seller was required to hold the contract documentation in escrow and was forbidden to sign it until and unless either option was exercised.

When is a warning statement “attached” to a contract?

Section 366 of the Property Agents and Motor Dealers Act 2000 (Qld) provides that all contracts for the sale of residential property in Queensland (other than contracts formed on a sale by auction) should have “attached” as the first or top sheet a warning statement in the approved form. The section does not explain or define the meaning of the word “attached”. Further, the section does not contemplate the situation where the contract is faxed to a potential buyer for execution.

Can compensation be claimed under the standard commercial land and building contract where the property sold has no legally enforceable vehicular access?

This was the question that confronted Wilson J in Jarema Pty Ltd v Michihiko Kato [2004] QSC 451. Facts The plaintiff was the buyer of a commercial property at Bundall. The property comprised a 6 storey office building with a basement car park with 54 car parking spaces. The property was sold for $5 million with the contract being the standard REIQ/QLS form for Commercial Land and Buildings (2nd ed GST reprint). The contract provided for a “due diligence” period. During this period, the buyer’s solicitors discovered that there was no direct access from a public road to the car park entrance. Access to the car park was over a lot of which the Gold Coast City Council was the registered owner under a nomination of trustees, the Council holding the property on trust for car parking and town planning purposes. Due to the absence of a registered easement over the Council’s land, the buyer’s solicitors sought a reduction in the purchase price. The seller would not agree to this. Finally the sale was completed with the buyer reserving its rights to seek compensation.

Changes to the REIQ contract and conveyancing case law update

The Reference Schedule to the REIQ houses and land contract and the lots in a Community Titles Scheme (“CTS”) contract has been amended to contain provision for disclosure concerning the installation of an approved safety switch. This section will not be required to be completed if the land is vacant (in the case of the houses and land contract) or if the present use is a commercial use (in the case of the lots in a CTS contract).

Homodimerization controls the fibroblast growth factor 9 subfamily's receptor binding and heparan sulfate-dependent diffusion in the extracellular matrix

Uncontrolled fibroblast growth factor (FGF) signaling can lead to human diseases, necessitating multiple layers of self-regulatory control mechanisms to keep its activity in check. Herein, we demonstrate that FGF9 and FGF20 ligands undergo a reversible homodimerization, occluding their key receptor binding sites. To test the role of dimerization in ligand autoinhibition, we introduced structure-based mutations into the dimer interfaces of FGF9 and FGF20. The mutations weakened the ability of the ligands to dimerize, effectively increasing the concentrations of monomeric ligands capable of binding and activating their cognate FGF receptor in vitro and in living cells. Interestingly, the monomeric ligands exhibit reduced heparin binding, resulting in their increased radii of heparan sulfate-dependent diffusion and biologic action, as evidenced by the wider dilation area of ex vivo lung cultures in response to implanted mutant FGF9-loaded beads. Hence, our data demonstrate that homodimerization autoregulates FGF9 and FGF20's receptor binding and concentration gradients in the extracellular matrix. Our study is the first to implicate ligand dimerization as an autoregulatory mechanism for growth factor bioactivity and sets the stage for engineering modified FGF9 subfamily ligands, with desired activity for use in both basic and translational research.