Long interspersed nuclear element 1 is an autonomous non-long terminal repeat 
retrotransposon that comprises ∼17% of the human genome. Its spontaneous 
retrotransposition and the accumulation of heritable L1 insertions can 
potentially result in genome instability and sporadic disorders. Moloney 
leukemia virus 10 homolog (MOV10), a putative RNA helicase, has been implicated 
in inhibiting L1 replication, although its underlying mechanism of action 
remains obscure. Moreover, the physiological relevance of MOV10-mediated L1 
regulation in human disease has not yet been examined. Using a proteomic 
approach, we identified RNASEH2 as a binding partner of MOV10. We show that 
MOV10 interacts with RNASEH2, and their interplay is crucial for restricting L1 
retrotransposition. RNASEH2 and MOV10 co-localize in the nucleus, and RNASEH2 
binds to L1 RNAs in a MOV10-dependent manner. Small hairpin RNA-mediated 
depletion of either RNASEH2A or MOV10 results in an accumulation of L1-specific 
RNA-DNA hybrids, suggesting they contribute to prevent formation of vital L1 
heteroduplexes during retrotransposition. Furthermore, we show that 
RNASEH2-MOV10-mediated L1 restriction downregulates expression of the rheumatoid 
arthritis-associated inflammatory cytokines and matrix-degrading proteinases in 
synovial cells, implicating a potential causal relationship between them and 
disease development in terms of disease predisposition.