Repair of \u3cem\u3eO\u3c/em\u3e\u3csup\u3e6\u3c/sup\u3e-Methylguanine Adducts in Human Telomeric G-Quadruplex DNA by \u3cem\u3eO\u3c/em\u3e\u3csup\u3e6\u3c/sup\u3e-Alkylguanine-DNA Alkyltransferase

O6-alkylguanine-DNA alkyltransferase (AGT) is a single-cycle DNA repair enzyme that removes pro-mutagenic O6-alkylguanine adducts from DNA. Its functions with short single-stranded and duplex substrates have been characterized, but its ability to act on other DNA structures remains poorly understood. Here, we examine the functions of this enzyme on O6-methylguanine (6mG) adducts in the four-stranded structure of the human telomeric G-quadruplex. On a folded 22-nt G-quadruplex substrate, binding saturated at 2 AGT:DNA, significantly less than the ~ 5 AGT:DNA found with linear single-stranded DNAs of similar length, and less than the value found with the telomere sequence under conditions that inhibit quadruplex formation (4 AGT:DNA). Despite these differences, AGT repaired 6mG adducts located within folded G-quadruplexes, at rates that were comparable to those found for a duplex DNA substrate under analogous conditions. Repair was kinetically biphasic with the amplitudes of rapid and slow phases dependent on the position of the adduct within the G-quadruplex: in general, adducts located in the top or bottom tetrads of a quadruplex stack exhibited more rapid-phase repair than did adducts located in the inner tetrad. This distinction may reflect differences in the conformational dynamics of 6mG residues in G-quadruplex DNAs

A male infant with Xq22.2q22.3 duplication containing PLP1 and MID2

Abstract Background The Xq22.2 q23 is a complex genomic region which includes the genes MID2 and PLP1 associated with FG syndrome 5 and Pelizaeus–Merzbacher disease, respectively. There is limited information regarding the clinical outcomes observed in patients with deletions within this region. Methods We report on a male infant with intrauterine growth retardation (IUGR) who developed head titubation and spasticity during his postnatal hospital course. Results Chromosome microarray revealed a 6.7 Mb interstitial duplication of Xq22.2q22.3. Fluorescence in situ hybridization showed that the patient's mother also possessed the identical duplication in the Xq22.3q22.3 region. Among the 34 OMIM genes in this interval, the duplication of the PLP1 (OMIM# 300401) and MID2 (OMIM# 300204) appears to be the most significant contributors to the patient's clinical features. Mutations and duplications of PLP1 are associated with X‐linked recessive Pelizaeus–Merzbacher disease (PMD). A single case of a Xq22.3 duplication including the MID2 has been reported in boy with features of FG syndrome. However, our patient's clinical features are not consistent with the FG syndrome phenotype. Conclusion Our patient's clinical features appear to be influenced by the PLP1 duplication but the clinical effect of other dosage sensitive genes influencing brain development cannot be ruled out