8OU1

Crystal structure of the SPOC domain of mouse SPOCD1

Summary for 8OU1

• Entry DOI: 10.2210/pdb8ou1/pdb
• Descriptor: SPOC domain-containing protein 1, CITRATE ANION (3 entities in total)
• Functional Keywords: pirna piwi dna methylation germline, gene regulation
• Biological source: Mus musculus (house mouse)
• Total number of polymer chains: 2
• Total formula weight: 32911.39

Authors

Heep, M.,Cook, A.G.,O'Carroll, D. (deposition date: 2023-04-21, release date: 2024-02-21, Last modification date: 2024-04-03)

Primary citation

Zoch, A.,Konieczny, G.,Auchynnikava, T.,Stallmeyer, B.,Rotte, N.,Heep, M.,Berrens, R.V.,Schito, M.,Kabayama, Y.,Schopp, T.,Kliesch, S.,Houston, B.,Nagirnaja, L.,O'Bryan, M.K.,Aston, K.I.,Conrad, D.F.,Rappsilber, J.,Allshire, R.C.,Cook, A.G.,Tuttelmann, F.,O'Carroll, D.
C19ORF84 connects piRNA and DNA methylation machineries to defend the mammalian germ line.
Mol.Cell, 84:1021-, 2024

PubMed Abstract: In the male mouse germ line, PIWI-interacting RNAs (piRNAs), bound by the PIWI protein MIWI2 (PIWIL4), guide DNA methylation of young active transposons through SPOCD1. However, the underlying mechanisms of SPOCD1-mediated piRNA-directed transposon methylation and whether this pathway functions to protect the human germ line remain unknown. We identified loss-of-function variants in human SPOCD1 that cause defective transposon silencing and male infertility. Through the analysis of these pathogenic alleles, we discovered that the uncharacterized protein C19ORF84 interacts with SPOCD1. DNMT3C, the DNA methyltransferase responsible for transposon methylation, associates with SPOCD1 and C19ORF84 in fetal gonocytes. Furthermore, C19ORF84 is essential for piRNA-directed DNA methylation and male mouse fertility. Finally, C19ORF84 mediates the in vivo association of SPOCD1 with the de novo methylation machinery. In summary, we have discovered a conserved role for the human piRNA pathway in transposon silencing and C19ORF84, an uncharacterized protein essential for orchestrating piRNA-directed DNA methylation.

PubMed: 38359823
DOI: 10.1016/j.molcel.2024.01.014

Experimental method

X-RAY DIFFRACTION (1.7 Å)