The SAGA Deubiquitination Module Promotes DNA Repair and Class Switch Recombination through ATM and DNAPK-Mediated γH2AX Formation

Summary: Class switch recombination (CSR) requires activation-induced deaminase (AID) to instigate double-stranded DNA breaks at the immunoglobulin locus. DNA breaks activate the DNA damage response (DDR) by inducing phosphorylation of histone H2AX followed by non-homologous end joining (NHEJ) repair. We carried out a genome-wide screen to identify CSR factors. We found that Usp22, Eny2, and Atxn7, members of the Spt-Ada-Gcn5-acetyltransferase (SAGA) deubiquitination module, are required for deubiquitination of H2BK120ub following DNA damage, are critical for CSR, and function downstream of AID. The SAGA deubiquitinase activity was required for optimal irradiation-induced γH2AX formation, and failure to remove H2BK120ub inhibits ATM- and DNAPK-induced γH2AX formation. Consistent with this effect, these proteins were found to function upstream of various double-stranded DNA repair pathways. This report demonstrates that deubiquitination of histone H2B impacts the early stages of the DDR and is required for the DNA repair phase of CSR. : Activation-induced deaminase induces class switch recombination by inducing DNA breaks at the immunoglobulin locus. Ramachandran et al. showed that the SAGA deubiquitination module is critical for this process. They showed that this complex is required for optimal γH2AX formation and functions upstream of various double-stranded DNA repair pathways

Spillover Effects of Drug Safety Warnings on Health Behavior

Abstract: We examine the impact of new medical information on drug safety on preventive health behavior. We exploit the release of the findings of the Women's Health Initiative Study (WHIS) -the largest randomized controlled trial of women's health- which demonstrated in 2002 that long-term Hormone Replacement Therapy increases the risk of heart attacks, stroke, blood clots and breast cancer among healthy postmenopausal women. Because hormone replacement is a therapy exclusive to women, we estimate the spillover effects of the WHIS findings on health behavior by means of a difference-in-differences methodology using men of similar ages as the control group. Using data from the Behavioral Risk Factor Surveillance System for 1998-2007, we find statistically significant small negative spillovers on post-menopausal women's likelihood of having an annual checkup and choice of a healthy diet, as proxied by daily fruit consumption. Our results also indicate that the observed spillover effects of drug safety on health behavior were entirely driven by the less educated. These findings suggest that policies aimed at raising awareness on the safety of medications may have unintended spillover effects on health behavior and that these spillovers may contribute to the existing health disparities by education