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SUMMARY:Disentangling strand interactions in DNA damage and repair - Sarah
  Aitken\, MRC Toxicology Unit
DTSTART:20221018T113000Z
DTEND:20221018T123000Z
UID:TALK183902@talks.cam.ac.uk
CONTACT:Michael Boemo
DESCRIPTION:Cancers arise through the acquisition of oncogenic mutations a
 nd grow by clonal expansion. Here we reveal that most mutagenic DNA lesion
 s are not resolved into a mutated DNA base pair within a single cell cycle
 . Instead\, DNA lesions segregate\, unrepaired\, into daughter cells for m
 ultiple cell generations\, resulting in the chromosome-scale phasing of su
 bsequent mutations. Furthermore\, DNA replication across these persisting 
 lesions can produce multiple alternative alleles in successive cell divisi
 ons\, thereby generating both multiallelic and combinatorial genetic diver
 sity. We exploit our discovery of lesion segregation to reveal how strand-
 asymmetric processes such as replication\, transcription\, and protein int
 eractions shape DNA damage and repair. We demonstrate that replication ove
 r lesions produces almost identical collateral mutagenesis on the leading 
 and lagging strands. In transcription\, the triggering of repair is stocha
 stic with frequent lesion bypass by RNA-polymerase. Finally\, defining mul
 tiallelic variation patterns\, we examine patterns of mutations in accessi
 ble chromatin regions as well as transcription factor binding sites. These
  results provide insight into how strand asymmetric mechanisms underlie th
 e formation\, tolerance\, and repair of DNA damage and thus shape cancer g
 enome evolution.
LOCATION:Lecture Theatre\, Department of Pathology\, Tennis Court Road
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