1 research outputs found
The chromatin network helps prevent cancer-associated mutagenesis at transcription-replication conflicts
Genome instability is a feature of cancer cells, transcription being an important
source of DNA damage. This is in large part associated with R-loops, which
hamper replication, especially at head-on transcription-replication conflicts
(TRCs). Here we show that TRCs trigger a DNA Damage Response (DDR)
involving the chromatin network to prevent genome instability. Depletion of
the key chromatin factors INO80, SMARCA5 and MTA2 results in TRCs, fork
stalling and R-loop-mediated DNA damage which mostly accumulates at S/G2,
while histone H3 Ser10 phosphorylation, a mark of chromatin compaction, is
enriched at TRCs. Strikingly, TRC regions show increased mutagenesis in
cancer cells with signatures of homologous recombination deficiency,
transcription-coupled nucleotide excision repair (TC-NER) and of the AID/
APOBEC cytidine deaminases, being predominant at head-on collisions. Thus,
our results support that the chromatin network prevents R-loops and TRCs
from genomic instability and mutagenic signatures frequently associated
with cancer.MCIN/AEI/10.13039/501100011033 - I + D + i PID2019-104270GB-I00/BMCConsejo Europeo de Investigación - ERC2014 AdG669898 TARLOO