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Department of Biological Sciences

The Waldman lab published a new study in DNA repair

Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare genetic condition characterized by features of accelerated aging and a life expectancy of about fourteen years. HGPS is commonly caused by a point mutation in the LMNA gene that codes for lamin A, an essential component of the nuclear lamina. The HGPS mutation alters splicing of the LMNA transcript, leading to the production of a truncated, farnesylated form of lamin A termed Progerin. Progerin is also produced in small quantities in healthy individuals and has been implicated in normal aging. HGPS is associated with an accumulation of genomic DNA double-strand breaks, suggesting alteration of DNA repair. DSB repair normally occurs by either homologous recombination (HR), an accurate, templated form of repair, or by nonhomologous end-joining (NHEJ), a non-templated rejoining of DNA ends that can be error-prone. Over-expression of progerin correlates with increased NHEJ relative to HR, but the exact impact of Progerin on the nature of DNA end-joining remains unknown. In their new study titled "Corruption of DNA end-joining in mammalian chromosomes by progerin expression", graduate students Liza Joudeh and Alannah DiCintio, their undergraduate collaborators, and their mentor Dr. Alan Waldman used a novel model experimental system in mouse fibroblasts to show that progerin expression leads to a marked decrease in the frequency of precise end-joining with a concomitant increase in imprecise end-joining. Progerin reduces the use of microhomology during DNA end-joining and increases deletion size associated with DNA end-joining. Results from this work suggest that progerin expression compromises genome stability by corrupting interactions between complementary sequences at DNA termini during DNA repair. Such influences of progerin may impact genome stability and contribute to the aging process. A great study!

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