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SUMMARY:DNA damage response control by RNA and its therapeutic potential -
  Fabrizio d'Adda di Fagagna
DTSTART:20240604T110000Z
DTEND:20240604T120000Z
UID:TALK212281@talks.cam.ac.uk
CONTACT:90994
DESCRIPTION:Fabrizio d’Adda di Fagagna 1\, 2\n \n1 IFOM – the FIRC Ins
 titute for Molecular Oncology Foundation\, Milan\, Italy\n2 IGM-CNR – Is
 tituto di Genetica Molecolare-Consiglio Nazionale delle Ricerche\, Pavia\,
  Italy\n \nWe previously reported that DNA double-strand breaks (DSBs) tri
 gger the synthesis by RNA polymerase II of damage-induced long non-coding 
 RNA (dilncRNA) that can be processed into shorter DNA damage response RNAs
  (DDRNAs). Such transcripts are essential for full DDR activation and thei
 r inhibition by antisense oligonucleotides (ASO) allows site-specific inhi
 bition of DNA damage signalling and repair (Francia et al Nature 2012\, Mi
 chelini et al Nature Cell Biology 2017\, D’Alessandro et al Nature Commu
 nications 2018).\nWe recently discovered that such transcriptional events 
 depend on the assembly\nof seemingly fully functional transcriptional prom
 oters that include a complete RNA polymerase II preinitiation complex (PIC
 ). Absence or inactivation of any of these factors causes a reduction in t
 he activation of the DNA damage response (DDR) both in cells and in an in 
 vitro system that reconstitutes DDR activation events on nucleosomes. Impo
 rtantly\, dilncRNAs drive molecular crowding of DDR proteins\, such as 53B
 P1\, into globular structures that exhibit liquid–liquid phase-separatio
 n condensate properties (Pessina et al Nature Cell Biology 2019).\n \nTelo
 meres\, the ends of linear chromosomes\, progressively accumulate DNA dama
 ge during physiological and pathological aging. We recapitulated the above
 -described events at damaged telomeres (Rossiello et al. Nature Communicat
 ions 2017) and demonstrated that\, in independent animal models of acceler
 ated aging\, specific DDR inhibition at telomeres by ASO improves aging’
 s detrimental phenotypes and extends lifespan (Aguado et al. Nature Commun
 ications 2019). We are now extending these observations in a number of mod
 els of age-related human diseases\n \nMore recently we demonstrated that a
  subset of cancer types is selectively sensitive to the treatment with thi
 s ASO-mediated approach.\n
LOCATION:Jean Thomas Lecture theatre\, Sanger Building\, Tennis Court Road
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