DNA Damage Response and Repair in Boron Neutron Capture Therapy

Boron neutron capture therapy (BNCT) is an approach to the radiotherapy of solid tumors that was first outlined in the 1930s but has attracted considerable attention recently with the advent of a new generation of neutron sources. In BNCT, tumor cells accumulate 10B atoms that react with epithermal neutrons, producing energetic α particles and 7Li atoms that damage the cell’s genome. The damage inflicted by BNCT appears not to be easily repairable and is thus lethal for the cell; however, the molecular events underlying the action of BNCT remain largely unaddressed. In this review, the chemistry of DNA damage during BNCT is outlined, the major mechanisms of DNA break sensing and repair are summarized, and the specifics of the repair of BNCT-induced DNA lesions are discussed

Distinct Mechanisms of Target Search by Endonuclease VIII-like DNA Glycosylases

Proteins that recognize specific DNA sequences or structural elements often find their cognate DNA lesions in a processive mode, in which an enzyme binds DNA non-specifically and then slides along the DNA contour by one-dimensional diffusion. Opposite to the processive mechanism is distributive search, when an enzyme binds, samples and releases DNA without significant lateral movement. Many DNA glycosylases, the repair enzymes that excise damaged bases from DNA, use processive search to find their cognate lesions. Here, using a method based on correlated cleavage of multiply damaged oligonucleotide substrates we investigate the mechanism of lesion search by three structurally related DNA glycosylases—bacterial endonuclease VIII (Nei) and its mammalian homologs NEIL1 and NEIL2. Similarly to another homologous enzyme, bacterial formamidopyrimidine–DNA glycosylase, NEIL1 seems to use a processive mode to locate its targets. However, the processivity of Nei was notably lower, and NEIL2 exhibited almost fully distributive action on all types of substrates. Although one-dimensional diffusion is often regarded as a universal search mechanism, our results indicate that even proteins sharing a common fold may be quite different in the ways they locate their targets in DNA

Noncatalytic Domains in DNA Glycosylases

Many proteins consist of two or more structural domains: separate parts that have a defined structure and function. For example, in enzymes, the catalytic activity is often localized in a core fragment, while other domains or disordered parts of the same protein participate in a number of regulatory processes. This situation is often observed in many DNA glycosylases, the proteins that remove damaged nucleobases thus initiating base excision DNA repair. This review covers the present knowledge about the functions and evolution of such noncatalytic parts in DNA glycosylases, mostly concerned with the human enzymes but also considering some unique members of this group coming from plants and prokaryotes