Nature https://doi.org/10.1038/s41586-022-04767-1 (2022)
Chromothripsis is a mutational process that occurs when structures such as micronuclei (MN) and chromosome bridges form in cells. These structures have fragile nuclear envelopes that can easily rupture, exposing chromatin to the cytoplasm, which leads to DNA damage through an unknown process. Writing in Nature, the lab of David Pellman now presents a mechanism that underlies how most of the DNA can be damaged when exposed to the cytosol. This involves a cascade of events that starts with the accumulation of RNA–DNA hybrids in the MN. The authors find that these RNA–DNA hybrids are edited by ADARs (adenine deaminases enzymes that act on RNA) to generate deoxyinosine on the DNA strand (as well as inosine on the RNA). These deoxyinosines are then converted to abasic sites by a DNA base-excision repair (BER) glycosylase, MPG (N-methyl-purine DNA glycosylase, or AAG), that are in turn cleaved by the BER endonuclease APE1 (apurinic/apyrimidinic endonuclease), creating single-stranded DNA nicks. Previous studies have shown that these single-stranded breaks can be converted to DNA double-stranded breaks by DNA replication or by ligation of close nicks in opposite strands. Thus, the model proposed presents an elegant mechanism by which chromosome fragmentation can occur due to pathological BER activity on the cytoplasm-exposed DNA. While it is not understood how the RNA–DNA hybrids form, preliminary data suggest this might be due to aberrant transcription in the MN that results in R-loop accumulation. Although further mechanistic studies will be needed to complete the picture on the mechanisms underlying chromothripsis, this study provides an important piece of the puzzle.
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