《all and end all》.pdfVIP

Nuclear Envelope Disease and Chromatin Organization 2009 281 Lamin A-linked progerias: is farnesylation the be all and end all? Dawn T. Smallwood and Sue Shackleton1 Department of Biochemistry, Henry Wellcome Building, University of Leicester, Leicester LE1 9HN, U.K. Abstract HGPS (Hutchinson–Gilford progeria syndrome) is a severe childhood disorder that appears to mimic an accelerated aging process. The disease is most commonly caused by gene mutations that disrupt the normal post-translational processing of lamin A, a structural component of the nuclear envelope. Impaired processing results in aberrant retention of a farnesyl group at the C-terminus of lamin A, leading to altered membrane dynamics. It has been widely proposed that persistence of the farnesyl moiety is the major factor responsible for the disease, prompting clinical trials of farnesyltransferase inhibitors to prevent lamin A farnesylation in children afflicted with HGPS. Although there is evidence implicating farnesylation in causing some of the cellular defects of HGPS, results of several recent studies suggest that aberrant lamin A farnesylation is not the only determinant of the disease. These findings have important implications for the design of treatments for this devastating disease. Introduction partners play a key role in many nuclear functions including HGPS (Hutchinson–Gilford progeria syndrome) is a rare chromatin organization, DNA replication, gene transcription inherited disorder with features reminiscent of premature and nuclear–cytoskeletal connection (reviewed in [6,7]). aging. A detailed de