High-efficiency bypass of DNA damage by human DNA polymerase Q

Endogenous DNA damage arises frequently, particularly apurinic (AP) sites. These must be dealt with by cells in order to avoid genotoxic effects. DNA polymerase theta; is a newly identified enzyme encoded by the human POLQ gene. We find that POLQ has an exceptional ability to bypass an AP site, inserting A with 22% of the efficiency of a normal template, and continuing extension as avidly as with a normally paired base. POLQ preferentially incorporates A opposite an AP site and strongly disfavors C. On nondamaged templates, POLQ makes frequent errors, incorporating G or T opposite T about 1% of the time. This very low fidelity distinguishes POLQ from other A-family polymerases. POLQ has three sequence insertions between conserved motifs in its catalytic site. One insert of approximately 22 residues into the tip of the polymerase thumb subdomain is predicted to confer considerable flexibility and additional DNA contacts to affect enzyme fidelity. POLQ is the only known enzyme that efficiently carries out both the insertion and extension steps for bypass of AP sites, commonly formed as endogenous genomic lesions.     

Chromatin modulation and the DNA damage response

The ability to sense and respond appropriately to genetic lesions is vitally important to maintain the integrity of the genome. Emerging evidence indicates that various modulations to chromatin structure are centrally important to many aspects of the DNA damage response (DDR). Here, we discuss recently described roles for specific post-translational covalent modifications to histone proteins, as well as ATP-dependent chromatin remodelling, in DNA damage signalling and repair of DNA double strand breaks.     

Epigenetic regulation of transcription by RNA polymerase III

Chromatin participates actively in all DNA transactions and all phenomena directly under the influence of chromatin are explained by epigenetic mechanisms. The genes transcribed by RNA polymerase (pol) III are generally found in regions free of nucleosomes, the structural units of chromatin. Yet, histone modifications and positions of nucleosomes in the gene flanking regions have been reported to show direct correlation with activity status of these genes. Gene-specific as well as genome-wide studies have also revealed association of several epigenetic components with pol III-transcribed genes. This review presents a summary of the research in past many years, which have gathered enough evidence to conclude that pol III-transcribed genes are important components of an epigenome.