Sudden cardiac death and channelopathies.

In Europe, the United States, and much of developed society, sudden cardiac death remains the biggest killer. Although many of these cases are due to known causes, such as atherosclerosis and myocardial infarction, some cases will not have clear findings at necropsy. Unexplained sudden death with an unremarkable autopsy is not rare, and the coroner or pathologist should consider genetically associated causes of disease, as discussed below. We will discuss the clinical presentation; genetic, molecular, and cellular abnormalities; and diagnostic evaluation of these causes, including ion channelopathies and cardiomyopathies (see list below). These diseases should be considered when there is no clear cause for death. Because these disorders have a genetic basis, other family members (who are still living and could seek treatment) could also be affected

Human RECQ1 promotes restart of replication forks reversed by DNA topoisomerase I inhibition

Topoisomerase I (TOP1) inhibitors are an important class of anticancer drugs. The cytotoxicity of TOP1 inhibitors can be modulated by replication fork reversal through a process that requires poly(ADP-ribose) polymerase (PARP) activity. Whether regressed forks can efficiently restart and what factors are required to restart fork progression after fork reversal are still unknown. We have combined biochemical and EM approaches with single-molecule DNA fiber analysis to identify a key role for human RECQ1 helicase in replication fork restart after TOP1 inhibition that is not shared by other human RecQ proteins. We show that the poly(ADP-ribosyl)ation activity of PARP1 stabilizes forks in the regressed state by limiting their restart by RECQ1. These studies provide new mechanistic insights into the roles of RECQ1 and PARP in DNA replication and offer molecular perspectives to potentiate chemotherapeutic regimens based on TOP1 inhibition