Документ взят из кэша поисковой машины. Адрес оригинального документа : http://mccmb.belozersky.msu.ru/2015/proceedings/abstracts/62.pdf Дата изменения: Mon Jun 15 15:40:08 2015 Дата индексирования: Sat Apr 9 23:26:20 2016 Кодировка:

APOBEC induced mutations are strongly enriched on the lagging strand during replication in human cancers
Vladimir B. Seplyarskiy1,2, Ruslan A. Soldatov3, Konstantin Y. Popadin4, Stylianos E. Antonarakis and Sergey I. Nikolaev
1 2 4 4

Institute of Information Transmission Problems, Russian Academy of Sciences, Moscow, Russia Pirogov Russian National Research Medical University, Ostrovitianov str. 1, Moscow, Russia, Department of Bioengineering and Bioinformatics, Moscow State University, Moscow, Russia Department of Genetic Medicine and Development, University of Geneva Medical School, 1 Rue

117997
3 4

Michel-Servet, 1211 Geneva, Switzerland; Institute of Genetics and Genomics in Geneva, 1211 Geneva, Switzerland

ABSTRACT Mutagenesis induced by deaminases of the APOBEC family is prevalent in many cancers. A fraction of APOBEC mutations is clustered around DSBs, however vast majority of them are dispersed over the genome1,2. Since APOBEC mutates specifically single stranded DNA (ssDNA)1
,3­6

we hypothesized that lagging DNA strand which exists in single strand state during

DNA replication may be a frequent target for APOBEC mutations. Knowing the direction of replication fork progression in human genome we were able predict for each genomic region which of the two DNA strands is lagging during replication7,8. We observed that APOBEC mutations exhibit a strong 1.96 fold bias towards lagging strand, suggesting that this is the major mechanism of generation of APOBEC mutations explaining more than 1/3 of cases. Additionally we report the 2.3 fold preference of APOBEC mutations for non-methylated cytosines then for 5-methylcytosine; and nearly complete absence of enrichment of APOBEC and non-APOBEC mutations in patients with APOBEC signature in late replication time. This research provides novel insights into the APOBEC mutagenesis and suggests mechanistic explanations for a considerable fraction of APOBEC induced mutations.