Nature research paper: Breakage of cytoplasmic chromosomes by pathological DNA base excision repair
Chromothripsis is a catastrophic mutational process that promotes tumorigenesis and causes congenital disease5–8, leading to DNA damage when chromatin is exposed to the interphase cytoplasm. Here, we identify a mechanism explaining a major fraction of this DNA damage. Micronuclei accumulate large amounts of RNA-DNA hybrids, which are edited by ADAR enzymes to generate deoxyinosine .
dI is then converted into abasic sites by a DNA base excision repair glycosylase, MPG , creating single-strand DNA nicks that can be converted to DNA double strand breaks by DNA replication or when closely spaced nicks occur on opposite strands. This model predicts that MPG should be able to remove the dI base from the DNA strand of RNA-DNA hybrids, which we demonstrate using pure proteins and oligonucleotide substrates.
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