COVALENT MODIFICATION OF PML BY THE SENTRIN FAMILY OF UBIQUITIN-LIKE PROTEINS

PML, a RING finger protein with tumor suppressor activity, has been im plicated in the pathogenesis of acute promyelocytic leukemia that aris es following a reciprocal chromosomal translocation that fuses the PML gene with the retinoic acid receptor alpha (RAR alpha) gene. Immunocy tochemical analysis has demonstrated that PML is co-localized with a n ovel ubiquitin-like protein in the nuclear bodies, which could be disr upted by the PML-RAR alpha: fusion protein. The physical nature of thi s co-localization is unknown. Using a COS cell expression system, we s how that PML is covalently modified by all three members of the sentri n family of ubiquitin-like proteins. Covalent modification of PML requ ires the conserved Gly residue near the C termini of sentrin proteins. Sentrinization of PML is highly specific because neither NEDD8 nor ub iquitin could modify PML. Similar specificity is also observed for the covalent modification of RanGAP1 by the sentrin member of ubiquitin-l ike proteins, These observations highlight the fine substrate specific ity of the sentrinization pathway. In acute promyelocytic leukemia, tw o forms of PML-RAR alpha fusion proteins have been reported, Remarkabl y, both forms of PML-RAR alpha fusion proteins could not be sentrinize d, Thus differential sentrinization of PML and PML-RAR alpha could pla y an important role in regulating the biological function of PML and i n the pathogenesis of acute promyelocytic leukemia.