Anxiety disorders and depression and risk for drug use disorders across the life course: Sex and ethnic contrasts

The present study examined the linkage between mental (i.e., anxiety disorders and depression) and drug use disorders in a multi-ethnic (i.e., 25% Euro-American, 38% Hispanic/Latino, 33% African American, 4% other) sample of adults (N = 1638, age 18–93 years old). Risk for drug use disorders was examined, while attending to methodological issues of prior research including (1) psychiatric comorbidity, (2) variations in risk associated with sex, ethnicity, and age, and (3) temporal order between mental and drug use disorders. ^ Participants were assessed using the Composite International Diagnostic Interview (CIDI; World Health Organization, 1990). A life history calendar (Freedman et al., 1988) was used to aid the ordering of onsets of all disorders assessed. ^ Preliminary analysis indicated anxiety disorders and depression were significant predictors of drug use disorders, but after controlling for comorbidity and temporal order, anxiety disorders and depression were no longer predictive of drug use disorders. Findings are discussed in terms of their usefulness for prevention and treatment of drug use disorders. ^

Oxidative DNA Damage Modulates Trinucleotide Repeat Instability Via DNA Base Excision Repair

Trinucleotide repeat (TNR) expansion is the cause of more than 40 types of human neurodegenerative diseases such as Huntington’s disease. Recent studies have linked TNR expansion with oxidative DNA damage and base excision repair (BER). In this research, we provided the first evidence that oxidative DNA damage can induce CAG repeat deletion/contraction via BER. We found that BER of an oxidized DNA base lesion, 8-oxoguanine in a CAG repeat tract, resulted in the formation of a CTG hairpin at the template strand. DNA polymerase β (pol b) then skipped over the hairpin creating a 5’-flap that was cleaved by flap endonuclease 1 (FEN1) leading to CAG repeat deletion. To further investigate whether BER may help to shorten an expanded TNR tract, we examined BER in a CAG repeat hairpin loop. We found that 8-oxoguanine DNA glycosylase removed the oxidized base located in the loop region of the hairpin leaving an abasic site. Apurinic/apyrimidinic (AP) endonuclease 1 then incised the 5’-end of the abasic site leaving a nick in the loop. This further converted the hairpin into an intermediate with a 3’-flap and a 5’-flap. As a 5’-3’ endonuclease, FEN1 cleaved the 5’-flap, whereas a 3’-5’ endonuclease, Mus81/Eme1, removed the 3’-flap. The coordination between FEN1 and Mus81/Eme1 ultimately resulted in removal of a CAG repeat hairpin attenuating or preventing TNR expansion. To further explore if pol β bypass of an oxidized base lesion, 5’,8-cyclodeoxyadenosine, may affect TNR instability, we examined pol β DNA synthesis in bypassing this base lesion and found that the lesion preferentially induced TNR deletion during BER and Okazaki fragment maturation. The repeat deletion was mediated by the formation of a loop in the template strand induced specifically by the damage. Pol β then skipped over the loop structure creating a 5’-flap that was efficiently removed by FEN1 leading to repeat deletion. Our study demonstrates that pol β-mediated BER plays an important role in mediating TNR deletion and removing a TNR hairpin to prevent TNR expansion. Our research provides a molecular basis for further developing BER as a target for prevention and treatment of neurodegenerative diseases caused by TNR expansion.