Mechanism Of SAMHD1 Cancer-associated Mutations In Abnormal Activation Of Retrotransposon LINE-1

Long interspersed nuclear elements(LINE-1)is now considered as the only active autonomous mobile DNA in humans and has played a major role in disrupting the integrity of human genome.Movement of these LINE-1 sequences to new loci in the genome has the potential of causing sporadic cases of disease.SAM domain and HD domain with protein 1 contained(SAMHD1)is a dual-function enzyme containing both nuclease and deoxyribonucleoside triphosphate triphosphohydrolase(dNTPase)activity.It has been recently reported that SAMHD1 mutations are present in several human cancers,including colon cancer,leukemia,lymphoma,breast cancer and lung cancer.SAMHD1 expression is downregulated in various cancers,leading to an intracellular dNTP imbalance and genomic instability SAMHD1 has been reported to be a potent inhibitor of LINE-1 retro transposition,and SAMHD1 mutations are frequently associated with cancer development.SAMHD1 has the capacity to block LINE-1 retro transposition.However,it is relatively rare in scientific discussion about the mechanism,by which tumor-related SAMHD1 mutants inhibit LINE-1.To gain insights on whether cancer-related SAMHD1 mutants affect LINE-1 activity,we explored the biochemical and cellular properties of some human mutants known correlate with the development of cancer.Most of the tested SAMHD1 cancer-related mutations were defective in LINE-1 inhibition,which in turn may have resulted in activated LINE-1 in cancer cells.Interestingly we also found that SAMHD1 mutant K288 T was defective for dNTPase activity but showed potent activity against LINE-1 retrotransposition.These findings suggest that LINE-1 inhibition does not depend solely on the dNTPase activity of SAMHD1.In contrast,SAMHD1’s ability to inhibit ORF2p-mediated LINE-1 RNP reverse transcription was correlated with SAMHD1-mediated LINE-1 inhibition.Our results imply that being effective in LINE-1 suppression is a prerequisite for SAMHD1 or its mutants to be regulated by the phosphorylation status of T592.Tumor-related mutations impair SAMHD1’s ability to travel between the nucleus and the nucleus,but this change is not directly related to the difference in subcellular localization.The association between the SAMHD1 mutation and the line-1 reverser was determined using clinical tumor samples,LINE-1 retro transposition activities are associated with and fluctuate during cancer initiation and progression which might be related to the mutant of SAMHD1.Together,our data could expand the knowledge of mechanism on the modulation of LINE-1 retro transposition,and reveal the molecular mechanism of cancer and autoimmune disease,which may provide a new idea on looking for disease diagnosis and new drug development.