Tired of C19 preprints? Read this: My student @NadezdaVolkova1 & collaborators completely took apart how mutational signatures are sculpted by DNA damage and repair. We grew and sequenced > 2700 worms from 53 repair KO's exposed to 11 mutagens. Phew. 1/7
nature.com/articles/s4146…
nature.com/articles/s4146…
Analysing all different combinations, including wildtype and no treatment, allows to map the mutagenic contributions of damage and repair: 9/11 mutagens produce different mutational signatures depending on which repair pathways are acting. This involves 32/53 repair genes. 2/7
We can pin down which elements of a mutational signature are caused by which type of DNA alteration (the same mutagen often produces a variety) – and which repair pathway is involved in mending each type of lesion (usually many pathways operate jointly) 3/7
It also allows to quantify the fraction of mutations prevented and introduced by DNA repair. It turns out that error-prone translesion synthesis *causes* the majority of base substitutions for many genotoxins (as a tradeoff to prevent replication stalling and large deletions) 4/7
On the other end, nucleotide excision repair appears to be the big fixer, preventing up to 90% mutations across the entire spectrum (by removing the lesion before it becomes mutagenic). 5/7
The implications? Examples of interactions in cancer exist (temozolomide + MGMT; POLE + MMRD; APOBEC + BERD), but these are generally hard to map owing to unknown histories of exposure and repair status. Yet the aetiology of mutational signatures has a fundamental duality: 6/7
Signatures of DNA repair deficiencies reflect the typical damage a cell experienced over its lifetime. Conversely sig's linked to mutagenic exposures are dependent on the cell's DNA repair capacity at the time. As either end can move one should also expect signatures to vary. 7/7
Huge thanks to everyone who has contributed and of course to Bettina Meier, Victor Gonzalez and Anton Gartner who shouldered the Herculean task of crossing and growing all the different lineages!
