p53-binding protein 1 (53BP1) is known to be an important mediator of the DNA-damage response1, with di-methylation of histone H4 lysine 20 (H4K20me2) critical to the recruitment of 53BP1 to double strand breaks (DSBs)2,3. However, it is not clear how 53BP1 is specifically targeted to the sites of DNA damage, since the overall level of H4K20me2 does not seem to increase following DNA damage. It has been proposed that DNA breaks may cause exposure of methylated H4K20 previously buried within the chromosome, however experimental evidence for such a model is lacking. Here we found that H4K20 methylation actually increases locally upon the induction of DSBs and that methylation of H4K20 at DSBs is mediated by the histone methyltransferase (HMT) MMSET (also known as NSD2 or WHSC1). Downregulation of MMSET significantly decreases H4K20 methylation at DSBs and the subsequent accumulation of 53BP1. We further found that the recruitment of MMSET to DSBs requires the γH2AX-MDC1 pathway, specifically the interaction between the MDC1 BRCT domain and phosphorylated Ser102 of MMSET. Thus, we propose that a pathway involving γH2AX-MDC1-MMSET regulates the induction of H4K20 methylation on histones around DSBs which, in turn, facilitates 53BP1 recruitment.
infection-control/controlrecommendations.html 4. Verbeek JH, Rajamaki B, Ijaz S, et al. Personal protective equipment for preventing highly infectious diseases due to exposure to contaminated body fluids in healthcare staff.
IMPORTANCE Functional outcomes have value for older adults who undergo surgical procedures. Preventing postoperative functional decline in this patient population necessitates the identification of the factors associated with this outcome and minimizing their implications.OBJECTIVES To assess the prevalence of functional decline 30 days after a surgical procedure among older adults 80 years or older, examine the risk factors of this decline, and identify ways to minimize this decline by addressing its mutable factors.
DESIGN, SETTING, AND PARTICIPANTSThis retrospective cohort study used patient data from the Geriatric Surgery Pilot Project, a multi-institutional data registry of the American College of Surgeons National Surgical Quality Improvement Program. Inclusion criteria were patients 80 years or older who underwent a surgical procedure that required an inpatient stay at 1 of 23 hospitals enrolled in the
Structural information about biological macromolecules near the atomic scale provides important insight into the functions of these molecules. To date, X-ray crystallography has been the predominant method used for macromolecular structure determination. However, challenges exist when solving structures with X-rays, including the phase problem and radiation damage. X-ray-free electron lasers (X-ray FELs) have enabled collection of diffraction information before the onset of radiation damage, yet the majority of structures solved at X-ray FELs have been phased using external information via molecular replacement. De novo phasing at X-ray FELs has proven challenging due in part to per-pulse variations in intensity and wavelength. Here we report the solution of a selenobiotinyl-streptavidin structure using phases obtained by the anomalous diffraction of selenium measured at a single wavelength (Se-SAD) at the Linac Coherent Light Source. Our results demonstrate Se-SAD, routinely employed at synchrotrons for novel structure determination, is now possible at X-ray FELs.
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