Séminaire : « When RNA meets DNA… Not always a good thing »

« When RNA meets DNA… not always a good thing»

Abstract

Ribonucleotides are the most common non-canonical nucleotides in the genome, resulting from misincorporation by DNA polymerases. However, cleavage by RNase H2 initiates their error-free removal by ribonucleotide excision repair (RER), thereby preventing mutagenesis and genome instability. Complete absence of RNase H2 in mammals causes wide-spread DNA damage and embryonic lethality, whereas partial loss-of-function mutations in RNase H2 genes cause the human autoinflammatory disorder Aicardi-Goutières syndrome, which mimics congenital viral infection of the brain. Through our work on this essential nuclease we have uncovered a link between genome instability and innate immune activation, and have shown that genome-embedded ribonucleotides are relevant to some cancers.

Key publications

Zimmermann M, Murina O, Reijns MAM, …, Jackson AP, Durocher D (2018) CRISPR screens identify genomic ribonucleotides as a source of PARP-trapping lesions. Nature

Mackenzie KJ, Carroll P,…, Reijns MAM*, Jackson AP* (2017) cGAS surveillance of micronuclei links genome instability to innate immunity. Nature

Mackenzie KJ,…, Reijns MAM, Jackson AP (2016) Ribonuclease H2 mutations induce a cGAS/STING-dependent innate immune response. EMBO J

Guenther C*, Kind B*, Reijns MAM*,…, Jackson AP, Lee-Kirsch MA (2015) Defective removal of ribonucleotides from DNA promotes systemic autoimmunity. J Clin Invest

Reijns MAM*, Kemp H*,…, Jackson AP, Taylor MS (2015) Lagging-strand replication shapes the mutational landscape of the genome. Nature

Reijns MAM*, Rabe B*,…, Jackson AP (2012) Enzymatic removal of ribonucleotides from DNA is essential for mammalian genome integrity and development. Cell