TY  - JOUR
AU  - Anderson, Craig J
AU  - Talmane, Lana
AU  - Luft, Juliet
AU  - Connelly, John
AU  - Nicholson, Michael D
AU  - Verburg, Jan C
AU  - Pich, Oriol
AU  - Campbell, Susan
AU  - Giaisi, Marco
AU  - Wei, Pei-Chi
AU  - Sundaram, Vasavi
AU  - Connor, Frances
AU  - Ginno, Paul A
AU  - Sasaki, Takayo
AU  - Gilbert, David M
AU  - López-Bigas, Núria
AU  - Semple, Colin A
AU  - Odom, Duncan
AU  - Aitken, Sarah J
AU  - Taylor, Martin S
TI  - Strand-resolved mutagenicity of DNA damage and repair.
JO  - Nature
VL  - 630
IS  - 8017
SN  - 0028-0836
CY  - London [u.a.]
PB  - Nature Publ. Group
M1  - DKFZ-2024-01258
SP  - 744-751
PY  - 2024
N1  - 2024 Jun;630(8017):744-751
AB  - DNA base damage is a major source of oncogenic mutations1. Such damage can produce strand-phased mutation patterns and multiallelic variation through the process of lesion segregation2. Here we exploited these properties to reveal how strand-asymmetric processes, such as replication and transcription, shape DNA damage and repair. Despite distinct mechanisms of leading and lagging strand replication3,4, we observe identical fidelity and damage tolerance for both strands. For small alkylation adducts of DNA, our results support a model in which the same translesion polymerase is recruited on-the-fly to both replication strands, starkly contrasting the strand asymmetric tolerance of bulky UV-induced adducts5. The accumulation of multiple distinct mutations at the site of persistent lesions provides the means to quantify the relative efficiency of repair processes genome wide and at single-base resolution. At multiple scales, we show DNA damage-induced mutations are largely shaped by the influence of DNA accessibility on repair efficiency, rather than gradients of DNA damage. Finally, we reveal specific genomic conditions that can actively drive oncogenic mutagenesis by corrupting the fidelity of nucleotide excision repair. These results provide insight into how strand-asymmetric mechanisms underlie the formation, tolerance and repair of DNA damage, thereby shaping cancer genome evolution.
LB  - PUB:(DE-HGF)16
C6  - pmid:38867042
DO  - DOI:10.1038/s41586-024-07490-1
UR  - https://inrepo02.dkfz.de/record/291025
ER  -